Sulfonamide derivatives

ABSTRACT

The present invention provides certain sulfonamide derivatives useful for potentiating glutamate receptor function in a patient and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.

This is a 371 of PCT/US01/04929 filed Feb. 26, 2001 which claimspriority to U.S. Provisional Application No. 60/188,806 filed Mar. 13,2000 and provisional application No. 60/234,651 filed Sep. 22, 2000.

BACKGROUND OF THE INVENTION

The present invention relates to the potentiation of glutamate receptorfunction using certain sulfonamide derivatives. It also relates to novelsulfonamide derivatives, to processes for their preparation and topharmaceutical compositions containing them.

In the mammalian central nervous system (CNS), the transmission of nerveimpulses is controlled by the interaction between a neurotransmitter,that is released by a sending neuron, and a surface receptor on areceiving neuron, which causes excitation of this receiving neuron.L-Glutamate, which is the most abundant neurotransmitter in the CNS,mediates the major excitatory pathway in mammals, and is referred to asan excitatory amino acid (EAA). The receptors that respond to glutamateare called excitatory amino acid receptors (EAA receptors). See Watkins& Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan,Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989);Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25(1990). The excitatory amino acids are of great physiologicalimportance, playing a role in a variety of physiological processes, suchas long-term potentiation (learning and memory), the development ofsynaptic plasticity, motor control, respiration, cardiovascularregulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types.Receptors that are directly coupled to the opening of cation channels inthe cell membrane of the neurons are termed “ionotropic”. This type ofreceptor has been subdivided into at least three subtypes, which aredefined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), andkainic acid (KA). The second general type of receptor is the G-proteinor second messenger-linked “metabotropic” excitatory amino acidreceptor. This second type is coupled to multiple second messengersystems that lead to enhanced phosphoinositide hydrolysis, activation ofphospholipase D, increases or decreases in c-AMP formation, and changesin ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci.,14, 13 (1993). Both types of receptors appear not only to mediate normalsynaptic transmission along excitatory pathways, but also participate inthe modification of synaptic connections during development andthroughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol.Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41 (1990).

AMPA receptors are assembled from four protein sub-units known as GluR1to GluR4, while kainic acid receptors are assembled from the sub-unitsGluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, MolecularPharmacology 44: 505-510, 1993. It is not yet known how these sub-unitsare combined in the natural state. However, the structures of certainhuman variants of each sub-unit have been elucidated, and cell linesexpressing individual sub-unit variants have been cloned andincorporated into test systems designed to identify compounds which bindto or interact with them, and hence which may modulate their function.Thus, European patent application, publication number EP-A2-0574257discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B.European patent application, publication number EP-A1-0583917 disclosesthe human sub-unit variant GluR4B.

One distinctive property of AMPA and kainic acid receptors is theirrapid deactivation and desensitization to glutamate. Yamada and Tang,The Journal of Neuroscience, September 1993, 13(9): 3904-3915 andKathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634-6647. Thephysiological implications of rapid desensitization, and deactivation ifany, are not fully understood.

It is known that the rapid desensitization and deactivation of AMPAand/or kainic acid receptors to glutamate may be inhibited using certaincompounds. This action of these compounds is often referred to in thealternative as “potentiation” of the receptors. One such compound, whichselectively potentiates AMPA receptor function, is cyclothiazide. Partinet al., Neuron. Vol. 11, 1069-1082, 1993.

International Patent Application Publication Number WO 9625926 disclosesa group of phenylthioalkylsulfonamides, S-oxides and homologs which aresaid to potentiate membrane currents induced by kainic acid and AMPA.

U.S. Pat. No. 3,143,549 discloses certain phenylalkylsulfamides,including 1-methyl-2-phenylethyl dimethylsulfamide. The compounds aresaid to have central nervous system activity, in particular anti-anxietyand tranquilizing properties.

U.S. Pat. No. 3,267,139 discloses certainN′-trimethylacetyl-N-phenylalkysulfamides and-phenylcyclopropylsulfamides having central nervous system activity andanticonvulsant activity. The compounds are also said to produceParkinson-like symptoms in experimental animals.

U.S. Pat. No. 3,860,723 discloses a method of increasing feed intake ofhealthy animals using certain phenylalkylsulfamides.

Foye et al., J. Pharm. Sci. (1971), 60(7), 1095-6 discloses certainphenylalkyl methylsulfonamides including N-1-methyl-2-phenylethylmethanesulfonamide, having hypotensive activity.

British Patent Specification Number 1,059,360 discloses certainphenylalkylsulfamides having activity as sedatives, narcotics andanti-convulsants, including1-(1-methyl-2-phenylethylaminosulphonyl)piperidine.

U.S. Pat. No. 4,210,749 discloses N-1-methyl-2-phenyl-3-methoxy ethylbutane-sulfonamide.

Gualtieri et al., J. Pharm. Sci., (1973), 62(5), 849-851 disclosesN-1-methyl-2-phenylethyl butanesulfonamide and its evaluation as amosquito repellent.

Foye et al., J. Pharm. Sci. (1979), 68(5), 591-5 disclosesN-1-methyl-2-(4-chlorophenyl)ethyl methane-sulfonamide.

Foye and Sane, J. Pharm. Sci. (1977), 66(7), 923-6 disclosesN-methanesulfonyl and N-trifluoromethanesulfonyl derivatives ofamphetamines and certain 4-substituted analogs thereof, and theirevaluation for central nervous system and anorexic effects.

European patent application publication no. EP-A1-0657442 disclosescertain naphthyloxyacetic acid derivatives as PEG2 agonists andantagonists. N-(2,2-dephenylethyl)-methanesulfonamide is disclosed as anintermediate at page 53, line 38.

U.S. Pat. No. 3,629,332 discloses certain N-aryl- and N-heteroarylalkylfluoroalkane sulfonamides as plant growth modifiers, includingN-(alpha-methylphenylethyl) trifluoromethanesulfonamide,difluoromethanesulfonamide and fluoromethanesulfonamide. Some of thecompounds are also said to have other biological activity, includinginsecticidal, acaricidal, nematicidal, analgesic and anti-inflammatoryactivity.

AMPA receptor potentiators have been shown to improve memory in avariety of animal tests. Staubli et al., Proc. Natl. Acad. Sci., Vol.91, pp 777-781, 1994, Neurobiology, and Arai et al., The Journal ofPharmacology and Experimental Therapeutics, 278: 627-638, 1996.

In addition, certain sulfonamide derivatives which potentiate glutamatereceptor function in a mammal have been disclosed in the followingInternational Patent Application Publications: WO 98/33496 publishedAug. 6, 1998; WO 99/43285 published Sep. 2, 1999; WO 00/06539; WO00/06537, WO 00/06176, WO 00/06159, WO 00/06158, WO 00/06157, WO00/06156, WO 00/06149, WO 00/06148, and WO 00/06083, all published Feb.10, 2000; and WO 00/66546 published Nov. 9, 2000.

The present invention provides compounds of formula I:

wherein

-   -   R¹ represents an unsubstituted or substituted aromatic group, or        an unsubstituted or substituted heteroaromatic group;    -   R² represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl,        chloro(1-6C)alkyl, (2-6C)alkenyl, phenyl which is unsubstituted        or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a        group of formula R³R⁴N in which R³ and R⁴ each independently        represents (1-4C)alkyl or, together with the nitrogen atom to        which they are attached form an azetidinyl, pyrrolidinyl,        piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or        octahydroazocinyl group;    -   R⁵ represents hydrogen, (1-6C)alkyl; (2-6C)alkenyl; or aryl; and    -   R⁶ represents hydrogen, (1-6C)alkyl; (2-6C)alkenyl; or aryl;        or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of potentiatingglutamate receptor function in a patient, which comprises administeringto said patient an effective amount of a compound of formula I.

The present invention provides a method of treating cognitive disordersin a patient, which comprises administering to said patient an effectiveamount of a compound of formula I.

The present invention provides a method of treating depression in apatient, which comprises administering to said patient an effectiveamount of a compound of formula I.

The present invention provides a method of treating Alzheimer's diseasein a patient, which comprises administering to said patient an effectiveamount of a compound of formula I.

In addition, the present invention further provides a method of treatingpsychosis or cognitive deficits associated with psychosis in a patient,which comprises administering to said patient an effective amount of acompound of formula I.

According to another aspect, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt thereof forthe manufacture of a medicament for potentiating glutamate receptorfunction.

In addition, the present invention provides the use of a compound offormula I or a pharmaceutically acceptable salt thereof for potentiatingglutamate receptor function.

The invention further provides pharmaceutical compositions comprising, acompound of formula I and a pharmaceutically acceptable diluent orcarrier.

This invention also encompasses novel intermediates, and processes forthe synthesis of the compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

In this specification, the term “potentiating glutamate receptorfunction” refers to any increased responsiveness of glutamate receptors,for example AMPA receptors, to glutamate or an agonist, and includes butis not limited to inhibition of rapid desensitization or deactivation ofAMPA receptors to glutamate.

A wide variety of conditions may be treated or prevented by thecompounds of formula I and their pharmaceutically acceptable saltsthrough their action as potentiators of glutamate receptor function.Such conditions include those associated with glutamate hypofunction,such as psychiatric and neurological disorders, for example cognitivedisorders; neuro-degenerative disorders such as Alzheimer's disease;age-related dementias; age-induced memory impairment; movement disorderssuch as tardive dyskinesia, Hungtington's chorea, myoclonus andParkinson's disease; reversal of drug-induced states (such as cocaine,amphetamines, alcohol-induced states); depression; attention deficitdisorder; attention deficit hyperactivity disorder; psychosis; cognitivedeficits associated with psychosis, drug-induced psychosis, and sexualdysfunction. The compounds of formula I may also be useful for improvingmemory (both short term and long term) and learning ability. The presentinvention provides the use of compounds of formula I for the treatmentof each of these conditions.

The present invention includes the pharmaceutically acceptable salts ofthe compounds defined by formula I. A compound of this invention canpossess a sufficiently acidic group, a sufficiently basic group, or bothfunctional groups, and accordingly react with any of a number of organicand inorganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. The term “pharmaceutically acceptablesalt” as used herein, refers to salts of the compounds of the aboveformula which are substantially non-toxic to living organisms. Typicalpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with apharmaceutically acceptable mineral or organic acid or an organic orinorganic base. Such salts are known as acid addition and base additionsalts. Such salts include the pharmaceutically acceptable salts listedin Journal of Pharmaceutical Science, 66, 2-19 (1977), which are knownto the skilled artisan. Acids commonly employed to form acid additionsalts are inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, phosphoric acid, and the like, andorganic acids such as p-toluenesulfonic, methanesulfonic acid,benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonicacid, succinic acid, citric acid, benzoic acid, acetic acid, and thelike. Examples of such pharmaceutically acceptable salts are thesulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate,caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride,isobutyrate, caproate, heptanoate, propiolate, propionate,phenylpropionate, salicylate, oxalate, malonate, succinate, suberate,sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate,nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate,teraphthalate, butyne-1,4-dioate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxybenzoate, naphthalene-2-benzoate, phthalate,p-toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate,xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate,phenylbutyrate, citrate, lactate, α-hydroxybutyrate, glycolate,tartrate, benzenesulfonate, methanesulfonate, ethanesulfonate,propanesulfonate, hydroxyethanesulfonate, 1-naphthalenesulfonate,2-napththalenesulfonate, 1,5-naphthalenedisulfonate, mandelate,tartarate, and the like. Preferred pharmaceutically acceptable acidaddition salts are those formed with mineral acids such as hydrochloricacid and hydrobromic acid, and those formed with organic acids such asmaleic acid, oxalic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that the above salts may form hydratesor exist in a substantially anhydrous form.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation: ${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the specific stereoisomersand enantiomers of compounds of formula I can be prepared by one ofordinary skill in the art utilizing well known techniques and processes,such as those disclosed by J. Jacques, et al., “Enantiomers, Racemates,and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel andS. H. Wilen, “Stereochemistry of Organic Compounds”, (Wiley-Interscience1994), and European Patent Application No. EP-A-838448, published Apr.29, 1998. Examples of resolutions include recrystallization techniquesor chiral chromatography.

Some of the compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

As used herein, the term “aromatic group” means the same as aryl, andincludes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and thelike.

The term “heteroaromatic group” includes an aromatic 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen, and a bicyclic group consisting of a 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen fused with a benzene ring or another 5-6 membered ringcontaining one to four atoms selected from oxygen, sulfur and nitrogen.Examples of heteroaromatic groups are thienyl, furyl, oxazolyl,isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl,isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, indolyl, and quinolyl.

The term “substituted” as used in the term “substituted aromatic orheteroaromatic group” herein signifies that one or more (for example oneor two) substituents may be present, said substituents being selectedfrom atoms and groups which, when present in the compound of formula I,do not prevent the compound of formula I from functioning as apotentiator of glutamate receptor function.

Examples of substituents which may be present in a substituted aromaticor heteroaromatic group group include halogen; nitro; cyano;hydroxyimino; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl;halo(1-10C)alkyl; (CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1to 4, X¹ represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO,OCONR¹³, R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl,(3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or(3-8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently representshydrogen or (1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together withthe nitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl;(1-4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴-(L^(a))_(n)-X²-(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, OCONR¹⁹,N(CO(1-4C)alkyl)CO, or NR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl,phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,(1-4C)alkylaminosulfonyl(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.

The term (1-10C)alkyl includes (1-8C)alkyl, (1-6C)alkyl and (1-4C)alkyl.Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

The term (2-10C)alkenyl includes (3-10C)alkenyl, (2-8C)alkenyl,(2-6C)alkenyl and (2-4C)alkenyl. Particular values are vinyl andprop-2-enyl.

The term (2-10C)alkynyl includes (3-10C)alkynyl, (2-8C)alkynyl,(2-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.

The term (3-8C)cycloalkyl, as such or in the term (3-8C)cycloalkyloxy,includes monocyclic and polycyclic groups. Particular values arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andbicyclo[2.2.2]octane. The term includes (3-6C)cycloalkyl: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

As used herein the terms “integer of from 1 to 4” or “integer of from 1to 3” includes the integers 1, 2, 3, and 4, or the integers 1, 2, and 3,respectively.

The term (5-8C)cycloalkyl includes cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

The term hydroxy(3-8C)cycloalkyl includes hydroxy-cyclopentyl, such as3-hydroxycyclopentyl.

The term oxo(3-8C)cycloalkyl includes oxocyclopentyl, such as3-oxocyclopentyl.

The terms “halogen”, “Hal” or “halide” include fluorine, chlorine,bromine and iodine unless otherwise specified.

The term halo(1-10C)alkyl includes halo(1-6C)alkyl, halo(1-4C)alkyl,fluoro(1-10C)alkyl, fluoro(1-6C)alkyl, fluoro(1-4C)alkyl,chloro(1-6C)alkyl and chloro(1-4C)alkyl, such as trifluoromethyl,2,2,2-trifluoroethyl, and chloromethyl.

The term (1-10C)alkoxy includes (1-6C)alkoxy and (1-4C)alkoxy, such asmethoxy, ethoxy, propoxy, isopropoxy and isobutoxy.

The term cyano(2-10C)alkenyl includes 2-cyanoethenyl.

The term (2-4C)alkylene includes ethylene, propylene and butylene. Apreferred value is ethylene.

The term thienyl includes thien-2-yl and thien-3-yl.

The term furyl includes fur-2-yl and fur-3-yl.

The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.

The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl andisoxazol-5-yl.

The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and[1,2,4]oxadiazol-5-yl.

The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.

The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.

The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and[1,2,4]thiadiazol-5-yl.

The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl andisothiazol-5-yl.

The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl andimidazolyl-5-yl.

The term triazolyl includes [1,2,4]triazol-3-yl and [1,2,4]triazol-5-yl.

The term tetrazolyl includes tetrazol-5-yl.

The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.

The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl,pyridazin-5-yl and pyridazin-6-yl.

The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl and pyrimidin-6-yl.

The term benzofuryl includes benzofur-2-yl and benzofur-3-yl.

The term benzothienyl includes benzothien-2-yl and benzothien-3-yl.

The term benzimidazolyl includes benzimidazol-2-yl.

The term benzoxazolyl includes benzoxazol-2-yl.

The term benzothiazolyl includes benzothiazol-2-yl.

The term indolyl includes indol-2-yl and indol-3-yl.

The term quinolyl includes quinol-2-yl.

The term dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl, and the term(1-4C)alkoxycarbonyidihydrothiazolyl includes4-methoxycarbonyl-4,5-dihydrothiazol-2-yl.

The term -(1-4C)alkyl(3-8C)cycloalkyl includes the following:

The term -(1-4C)alkylaromatic includes the following:

Examples of values for R² are methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl,chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl,4-fluorophenyl, or dimethylamino. Preferably R² is ethyl, 2-propyl ordimethylamino.

Examples of values for R⁹ are hydrogen, methyl, ethyl, propyl,isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2-pyrrolidinyl, morpholino or 2-tetrahydrofuryl.

R⁹ is preferably (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl,pyrrolidinyl, morpholino or tetrahydrofuryl.

Examples of values for R¹⁵ are hydrogen, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl,2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl,2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

X¹ preferably, represents O, CO, CONH or NHCO.

z is preferably 0.

Particular values for the groups (CH₂)_(y)X¹R⁹ and (CH₂)_(z)X³R¹⁵include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such asmethoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy,including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy,including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl,such as formyl and ethanoyl.

Examples of particular values for y are 0 and 1.

Examples of particular values for z are 0, 1, 2 and 3.

L^(a) and L^(b) preferably each independently represents CH₂.

X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH orOCH₂CONH, with a bond, O, and CONH being especially preferred.

Preferably the group (CH₂)_(y)X¹R⁹ represents CHO; COCH₃, OCH₃;OCH(CH₃)₂; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl,t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropylor cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.

Preferably the group (CH₂)_(z)X³R¹⁵ represents NH₂; CH₂NH₂; (CH₂)₂NH₂;(CH₂)₃NH₂; CONH₂; CONHCH₃; CON(CH₃)₂; N(C₂H₅)₂; CH₂OH; CH(OH)CH₃;CH(OH)CH₂CH₂; CHO; COCH₃; COOH; COOCH₃; CH₂NHCOOC(CH₃)₃;(CH₂)₂NHCOOC(CH₃)₃; SO₂NH₂; NHSO₂CH₃; NHSO₂CH(CH₃)₂,OCH(CH₃)CH₂NHSO₂CH(CH₃)₂, N(COCH₃)₂; a group of formula (CH₂)₂NHSO₂R¹⁵in which R¹⁵ represents CH₃, CH₂CH₃, CH(CH₃)₂, (CH₂)₂CH₃, (CH₃)₃CH₃,benzyl, CH₂CF₃, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl,phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-methoxyphenyl, 1-(2-dimethylamino)naphthyl or2-thienyl; CH(OH)CH₂NHSO₂CH₃; (CH₂)₃NHSO₂CH(CH₃)₂;COCH₂N(OCOC(CH₃)₂SO₂CH₃; COCH₂NHSO₂CH₃; (CH₂)₂NHCOR¹⁵ in which R¹⁵represents CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, phenyl, 3-fluorophenyl,4-fluorophenyl, benzyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-thienyl,CH═CH, CH═CHCN, OCH₃ or O(CH₂)₃CH₃.

Examples of particular values for (L^(a))_(n)-X²-(L^(b))_(m) are a bond,O, NH, S, SO, SO₂, CO, CH₂, COCH₂, COCONH, CH(OH)CH₂, CONH, NHCO,NHCONH, CH₂O, OCH₂, OCH₂CONH, CH₂NH, NHCH₂ and CH₂CH₂, with a bond,CONH, and CH₂O being especially preferred.

R¹⁴ is preferably an unsubstituted or substituted phenyl, naphthyl,furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidylbenzothienyl or benzothiazolyl group.

Examples of particular values for R¹⁴ are phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,4-iodophenyl, 2,3-difluoro-phenyl, 2,4-difluorophenyl,3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,4-cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl,4-methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl,2-prop-2-enylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-bromomethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl,2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetylphenyl,3-acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl,2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-butoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl,3-(1-hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl,2-(1-hydroxypropyl)phenyl, 4-(1-hydroxypropyl)phenyl,2-(1-hydroxy-2,2-dimethyl-propyl)phenyl, 4-trifluoromethoxyphenyl,2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl,4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3-aminopropyl)phenyl,4-carboxyphenyl, 4-carbamoylphenyl, 4-N-methylcarbamoylphenyl,4-N,N-dimethylcarbamoylphenyl, 2-isopropylaminomethylphenyl,4-t-butoxycarbonylaminomethylphenyl,4-(2-isopropoxy-carboxamido)ethylphenyl,4-(2-t-butoxycarboxamido)ethyl-phenyl, 4-isopropylsulfonylaminophenyl,4-(2-methane-sulfonylamino)ethylphenyl,4-(2-ethylsulfonylamino)ethyl-phenyl,4-(3-isopropylsulfonylamino)propylphenyl,4-(1-(2-(2-propane)sulfonylamino)propyl)phenyl,4-(2-propylsulfonyl-amino)ethylphenyl,4-(2-isopropylsulfonylamino)ethylphenyl,4-(2-butylsulfonylamino)ethylphenyl,4-(1-isopropyl-sulfonylaminomethyl)ethylphenyl,4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl,4-(2-(2,2,2-trifluoroethyl)-sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonylamino)-ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylamino)-ethylphenyl,4-(2-N,N-dimethylaminosulfonylamino)-ethylphenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluoro-phenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethyl-phenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoro-methylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(1-(2-(2-methoxy-carbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl,4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl,4-(N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl,4-(2-(2-thienylcarboxamido)ethyl)phenyl, thien-2-yl,5-hydroxy-methylthien-2-yl, 5-formylthien-2-yl, thien-3-yl,5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2-bromothien-3-yl,fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl,3-bromoisoxazol-5-yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl,5-methylisoxazol-3-yl, 5-hydroxymethylisoxazol-3-yl,5-methyl-3-phenylisoxazol4-yl, 5-(2-hydroxyethyl)isoxazol-3-yl,5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl,5-N-methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl,3-bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl,4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl,4-carboxythiazol-2-yl, imidazol-1-yl, 2-sulfhydryl-imidazol-1-yl,[1,2,4]triazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl,2-ethyltetrazol-5-yl, 2-isopropyl-tetrazol-5-yl,2-(2-propenyl)tetrazol-5-yl, 2-benzyl-tetrazol-5-yl, pyrid-2-yl,5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid4-yl,5-trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl,6-methylpyridazin-3-yl, 6-methoxypyrazin-3-yl, pyrimidin-5-yl,benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl.

Examples of an unsubstituted or substituted aromatic or heteroaromaticgroup represented by R¹ are unsubstituted or substituted phenyl, furyl,thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).

Examples of an unsubstituted or substituted (5-8C)cycloalkyl grouprepresented by R¹ are unsubstituted or substituted cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl, with cyclohexyl being preferred.

More preferably, R¹ represents 2-naphthyl or a group of formula:

in which

-   -   R²⁰ represents halogen; nitro; cyano; hydroxyimino;        (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl;        hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;        (CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹        represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO,        OCONR¹³, R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl,        (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or        (3-8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently        represents hydrogen or (1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or        R¹³ together with the nitrogen atom to which they are attached        form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino        group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C)alkylpiperazinyl;        thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl;        thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl;        dihydrothienyl; dihydrofuryl; dihydrothiopyranyl;        dihydropyranyl; dihydrothiazolyl;        (1-4C)alkoxycarbonyl-dihydrothiazolyl;        (1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl;        tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl;        tetrahydropyranyl; indolyl; benzofuryl; benzothienyl;        benzimidazolyl; benzothiazolyl; and a group of formula        R¹⁴-(L^(a))_(n)-X²-(L^(b))_(m) in which X² represents a bond, O,        NH, S, SO, SO₂, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH,        OCH₂CONH or CH═CH, NHCO, L^(a) and L^(b) each represent        (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and        R¹⁴ represents a phenyl or hetero-aromatic-group which is        unsubstituted or substituted by one or two of halogen; nitro;        cyano; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl;        (3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);        halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; (CH₂)_(z)X³R¹⁵ in        which z is 0 or an integer of from 1 to 4, X³ represents O, S,        NR¹⁶, CO, CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷,        NHCONH, OCONR¹⁹, N(CO(1-4C)alkyl)CO, or NR¹⁹COO, R¹⁵ represents        hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl,        (1-4C)alkoxycarbonyl(1-4C)alkyl,        (1-4C)alkylsulfonylamino(1-4C)alkyl,        (1-4C)alkylaminosulfonyl(1-4C)alkyl,        (N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,        (3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or        an aromatic or heteroaromatic group which is unsubstituted or        substituted by one or two of halogen, (1-4C)alkyl,        halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶,        R¹⁷, R¹⁸ and R¹⁹ each independently represents hydrogen or        (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷, R¹⁸ or R¹⁹ together with the        nitrogen atom to which they are attached form an azetidinyl,        pyrrolidinyl, piperidinyl or morpholino group; and    -   R²¹ represents a hydrogen atom, a halogen atom, a (1-4C)alkyl        group or a (1-4C)alkoxy group.

Examples of particular values for R²⁰ are fluorine, chlorine, bromine,cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, 1,1-dimethylethyl, cyclopentyl, cyclohexyl,3-hydroxycyclopentyl, 3-oxocyclopentyl, methoxy, ethoxy, propoxy,2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido,1-butanoylamido, t-butylcarboxamido, acryloylamido,2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy,morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido,cyclobutylcarboxamido, cyclopentyl-carboxamido, cyclohexylcarboxamido,cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino,piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2-yl,4,5-dihydro-4-methoxy-carbonyl-5,5-dimethylthiazol-2-yl,benzothien-2-yl, benzothiazol-2-yl, phenyl, 2-fluorophenyl,3-fluorophenyl, 2,3-difluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 2-methylphenyl,4-methylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,3-trifluoromethylphenyl, 4-trifluoro-methylphenyl, 4-(2-cyanoethenyl,2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 3-acetyl-phenyl,4-acetylphenyl, 4-carboxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl,2-hydroxymethyphenyl, 4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl,4-(1-hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl,4-(2-aminoethyl)-phenyl, 4-(3-aminopropyl)phenyl,4-(2-acetylaminoethyl)-phenyl, 4-t-butoxycarboxylaminoethyl)phenyl,4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino,4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonyl-aminoethyl)phenyl,4-(2-ethylsulfonylaminoethyl)phenyl,4-(2-propylsulfonylaminoethyl)phenyl,4-(2-butylsulfonyl-aminoethyl)phenyl,4-(2-isopropylsulfonylaminoethyl)phenyl,4-(1-hydroxy-2-methanesulfonylaminoethyl)phenyl,4-(2-dimethylaminosulfonylaminoethyl)phenyl,4-(1-(2-(2-propyl)sulfonylaminopropyl)phenyl,4-(2-(2,2,2-trifluoro-ethyl)sulfonylaminopropyl)phenyl,4-(2-cyclohexylsulfonyl-aminoethyl)phenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethyphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4-carbamoylphenyl,4-methyl-carbamoylphenyl, 4-dimethylcarbamoylphenyl,4-(2-(2-methylpropaneamido)ethyl)phenyl,4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido,2-fluorobenzamido, 3-flurobenzamido, 4-fluorobenzamido,2,4-difluorobenzamido, 3-chlorobenzamido, 4-chlorobenzamido,4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3-methylbenzamido,4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido,4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido,3-trifluoromethylbenzamido, 4-trifluoromethylbenzamido,2-fluoro-4-trifluoromethyl-benzamido, 2-methoxybenzamido,3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido,4-phenylphenyl-carboxamido, 4-benzylcarboxamido,4-phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy,2-fluoro-benzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonylamino)ethyl)phenyl,4-(2-phenylacetamido)-ethyl)phenyl,4-(methanesulfonylaminoethanoyl)phenyl,4-(N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl,2-thienylcarboxamido, 2-furylcarboxamido,3-(5-methyl-isoxazolyl)carboxamido, 5-isoxazolylcarboxamido,2-benzothienylcarboxamido, 4-(5-methyl-3-phenylisoxazolyl)-carboxamido,4-pyridylcarboxamido, 2-(5-nitrofuryl)-carboxamido,2-pyridylcarboxamido, 6-chloro-2-pyridyl-carboxamido,2-thienysulfonamido, 2-thienylmethylamino, 3-thienylmethylamino,2-furylmethylamino, 3-furylmethylamino, 3-acetylureido and2-(2-thienyl)ethylureido.

Examples of particular values for R²¹ are hydrogen and chlorine. R²¹ ispreferably ortho to R²⁰.

Examples of particular values for R¹ are 2-naphthyl, 4-bromophenyl,4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl-phenyl,4-isobutylphenyl, 4-t-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl,4-cyclopentyphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl,4-(4-hydroxymethylphenyl)-phenyl, 4-(2-furyl)phenyl, 4-(3-furyl)phenyl,4-(2-thienyl)-phenyl, 4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl,4-(piperidin-I-yl)phenyl, 3-chloro-4-piperidin-1-ylphenyl,4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3-fluoro-phenyl)phenyl,4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl,4-(4-formylphenyl)phenyl, 4-(4-methylphenyl)phenyl, and4-(2-methoxyphenyl)phenyl.

It is understood that compounds of the formulas If, Ig, and Ih:

wherein

-   -   z is 0, or an integer 1, 2, 3 or 4;    -   R^(15a) represents (1-6C)alkyl, fluoro(1-4C)alkyl, or phenyl        which is unsubstituted or substituted by one or two of halogen,        (1-4C)alkyl, halo(1-4C)alkyl, and (1-4C)alkoxy; and    -   R^(1a) and R^(1b) each independently represent hydrogen,        halogen; nitro; cyano; (1-10C)alkyl; halo(1-10C)alkyl; phenyl;        thienyl; (CH₂)_(z)X³R^(15b) in which z is 0 or an integer 1, 2,        3, or 4, X³ represents O, S, NR¹⁶, CO, COO, OCO, R^(15b)        represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,        halo(1-10C)alkyl, (3-10C)alkenyl, or phenyl which is        unsubstituted or substituted by one or two of halogen,        (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and        (1-4C)alkoxy; and    -   R¹⁶ represents hydrogen or (1-10C)alkyl;    -   or a pharmaceutically acceptable salt thereof;    -   are included within the scope of the present invention and are        particularly preferred.

Preferably, in formula If, R^(1a) is hydrogen and R^(1b) is methyl,methoxy, fluoro, chloro, cyano, NH₂, —CH₂NH₂, —CH₂CH₂NH₂, 2-thienyl,3-thienyl, —CHO, trifluoromethyl, —CH₂CN, —CO₂CH₃, or —CO₂CH₂CH₃; orR^(1a) and R^(1b) are both hydrogen, fluoro, or chloro.

Preferably, in formulas Ig and Ih, R^(15a) respresents methyl, ethyl,isopropyl, or trifluoromethyl.

Preferably, in formulas Ig and Ih, z represents 0, 1 or 2.

The compounds of formula I can be prepared as set forth in Scheme I. Thereagents and starting materials are readily available to one of ordinaryskill in the art. All substituents, unless otherwise specified are aspreviously defined.

In Scheme I, step A the compound of structure (1) is O-alkylated withthe compound of structure (2). For example, at room temperature,compound (1) is dissolved in a suitable organic solvent, such asN,N-dimethylformamide and added to about 1.0 to about 1.1 equivalents ofa suitable base, such as sodium hydride in N,N-dimethylformamide. Thereaction mixture is stirred for about 30 minutes to about 2 hours andabout one equivalent of compound (2), wherein Hal represents Br or Cland R represents H or (1-10C)alkyl, dissolved in N,N-dimethylformamideis added dropwise to the reaction mixture. This is followed by additionof about 1.2 equivalents of sodium iodide. The reaction mixture is thenheated at reflux for about 2 to 6 hours and then allowed to cool to roomtemperature. The ether (3) is then isolated and purified by techniqueswell known in the art, such as extraction techniques and chromatography.For example, the cooled reaction mixture is diluted with water andextracted with a suitable organic solvent, such as ethyl acetate. Theorganic extracts are combined, washed with water, dried over potassiumcarbonate, filtered, and concentrated under vacuum to provide the crudeether (3). This crude material is then purified by silica gelchromatography with a suitable eluent, such as hexanelethyl acetate(1:1) to provide the purified ether (3).

In Scheme I, step B, ether (3) is converted to the amide of structure(4) under standard conditions. For example, ether (3) is combined withan excess of ammonia (2M solution of ammonia in methanol for example) ina suitable organic solvent, such as tetrahydrofuran and the reactionmixture is stirred for about 24 to about 48 hours at room temperature.The reaction mixture is then concentrated under vacuum to provide theamide (4).

In Scheme I, step C, the amide (4) is reduced under conditions wellknown in the art to provide the amine of structure (5). For example, seeJerry March, “Advanced Organic Chemistry,” second edition, McGraw-HillBook Company, 1977, page 1122. More specifically, for example, amide (4)is dissolved in a suitable organic solvent, such as tetrahyrofuran andtreated with about 1 equivalent of a suitable reducing agent, such asborane-methyl sulfide complex. The reaction mixture is then heated atreflux for about 8 to 16 hours under a nitrogen atmosphere and thencooled to room temperature. The reaction is then quenched by addition ofa tetrahydrofuran/methanol (1:1) mixture until foaming ceases. Then 5Naqueous sodium hydroxide is added and the reaction is heated at refluxfor about 5 hours. The reaction is then allowed to cool and is extractedwith a suitable organic solvent, such as methylene chloride. The organicextracts are combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to provide the crude amine (5). This materialcan be converted to its corresponding HCl salt by dissolving the amine(5) in a suitable organic solvent, such as diethyl ether and treatingwith excess anhydrous HCl gas. The mixture is allowed to stir for about1 to 6 hours and the resulting precipitate is collected by filtration toprovide the amine (5) hydrochloride salt. Alternatively, the mixture canbe concentrated under vacuum to provide amine (5) hydrochloride salt.

In Scheme I, step D the amine (5) is sulfonylated under conditions wellknown in the art with a sulfonyl chloride of formula ClSO₂R² to providethe compound of formula I. For example, the amine (5) is dissolved in asuitable organic solvent, such as methylene chloride and treated with anexcess of a suitable organic base, such as triethylamine under anatmosphere of nitrogen. The solution is cooled to about 0° C. andtreated slowly with about 1.0 to 1.2 equivalents of a sulfonyl chlorideof formula ClSO₂R², and the reaction mixture is then allowed to warm toroom temperature and stirred for about 8 to 16 hours. The compound offormula I is then isolated and purified by techniques well known in theart. For example, the reaction mixture is quenched with water and theorganic phase is separated from the aqueous layer. The organic phase isthen dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to provide the crude compound of formula I. This crudematerial is then purified by silica gel chromatography with a suitableeluent, such as hexane/ethyl acetate (1:1) to provide the purifiedcompound of formula I.

The compounds of formula I in which R¹ represents a 4-bromophenyl groupmay be converted into other compounds of formula I in which R¹represents a 4-substituted alkyl- or cycloalkylphenyl group, such as4-cyclopentylphenyl by treatment of the corresponding bromide with anappropriate alkyl- or cycloalkyl Grignard reagent, such ascyclopentyl-magnesium bromide, in the presence of a palladium(II)catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)(PdCl₂(dppf)),in an aprotic solvent, such as diethyl ether at temperatures rangingfrom −78° C. to 25° C.

Alternatively, the compounds of formula I in which R¹ represents a4-bromophenyl group may be converted to a 4-(trimethylstannyl)phenyl or4-(tri-n-butylstannyl)phenyl group by treatment of the correspondingbromide with a palladium(0) catalyst, such astetrakis(triphenylphosphine)-palladium(0) and hexaalkyldistannane, wherethe alkyl group is methyl or n-butyl, in an aprotic solvent such astoluene in the presence of a tertiary amine base such as triethyl-amine,at temperatures ranging from 80 to 140° C., preferably from 90 to 110°C.

The compounds of formula I in which R¹ represents a4-(tri-n-butylstannyl)phenyl group may then be reacted with an aryl- orheteroarylbromide, such as 2-bromothiophene-5-carboxaldehyde, or anaryl- or heteroaryliodide, or an aryl- or heteroaryltriflate, in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), or a palladium(II) catalyst,such as bis(triphenylphosphine)-palladium(II) dichloride, in an aproticsolvent, such as dioxane, at temperatures ranging from 80 to 140° C.,preferably from 90 to 110° C., to afford the corresponding4-(aryl)phenyl or 4-(heteroaryl)phenyl substituted compound.

The compounds of formula I in which R¹ represents a 4-bromophenyl groupmay be converted into a 4-substitutedcarboxyaldehydephenyl(formylphenyl) group by reaction of thecorresponding bromide with the carbon monoxide gas which is bubbled intothe reaction under atmospheric pressure in the presence of apalladium(II) catalyst, such as bis(triphenyl-phosphine)palladium(II)dichloride and sodium formate in an aprotic solvent, such asdimethylformamide at temperatures ranging from 70 to 110° C., preferablyat 90° C.

The compounds of formula I in which R¹ represents a 4-hydroxyphenylgroup may be converted into other compounds of formula I in which R¹represents an alkoxy group by treatment of the correspondinghydroxyphenyl group with an appropriate alkyl halide such as benzylbromide in the presence of sodium hydride in an aprotic solvent such asdimethylformamide at temperatures ranging from 25 to 100° C., preferablyfrom 50 to 90° C.

More specifically, the compounds of formulas Ia and Ib can be preparedas set forth in Scheme II. The reagents and starting materials arereadily available to one of ordinary skill in the art. All substituents,unless otherwise specified are as previously defined.

In Scheme II, step A the compound of structure (1a) is O-alkylated withthe compound of structure (2) to provide the ether of structure (3a) ina manner analogous to the procedure set forth above in Scheme I, step A.

In Scheme II, step B, ether (3a) is converted to the amide of structure(4a) in a manner analogous to the procedure set forth above in Scheme I,step B.

In Scheme II, step C, the amide (4a) is reduced in a manner analogous tothe procedure described in Scheme I, step C above, to provide the amineof structure (5a).

In Scheme II, step D the amine (5a) is sulfonylated with a sulfonylchloride of formula ClSO₂R² to provide the compound of formula Ia in amanner analogous to the procedure set forth in Scheme I, step D above.

In Scheme II, step E, the compound of formula Ia is coupled with theboronic acid of structure (6), wherein R^(1a) and R^(1b) eachindependently represent hydrogen, halogen; nitro; cyano; (1-10C)alkyl;(2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;4-(1,1-dioxotetrahydro-1,2-thiazinyl); halo(1-10C)alkyl;cyano(2-10C)alkenyl; phenyl; thienyl; (CH₂)_(z)X³R¹⁵ in which z is 0 oran integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO,OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹ or NR¹⁹COO, R¹⁵represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl,(1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; underconditions well known in the art to provide the biphenyl compound offormula Ib. For example, see International Patent ApplicationPublication: WO 98/33496 published Aug. 6, 1998. More specifically, forexample, the compound of formula Ia is combined with about 1.0 to about1.2 equivalents of a boronic acid (6), a catalytic amount oftetrakis(triphenylphosphine)palladium(0), and an excess of a suitablebase, such as aqueous sodium carbonate, in a suitable organic solvent,such as 1,4-dioxane under an atmosphere of nitrogen. The reactionmixture is heated at reflux for about 8 to about 16 hours. Aftercooling, the reaction is then quenched with water and the compound offormula Ib is isolated and purified by techniques well known in the art,such as extraction techniques and silica gel chromatographyrespectively. For example, the quenched reaction is extracted with asuitable organic solvent, such as methylene chloride, the organicextracts are combined, dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum to provide crude compound of formula Ib.This crude material is then purified by silica gel chromatography with asuitable eluent, such as hexane/ethyl acetate (1:1) to provide thepurified compound of formula Ib.

Alternatively, in Scheme II, step E, the compound of formula Ia iscombined with about 1.1 to about 1.2 equivalents of a boronic acid (6),a catalytic amount of dichlorobis(triphenylphosphine)palladium (II), andan excess of a suitable base, such as aqueous sodium carbonate, in asuitable organic solvent, such as 1,2-dimethoxyethane under anatmosphere of nitrogen. The reaction mixture is heated at reflux forabout 8 to about 16 hours. After cooling, the reaction is then quenchedwith water and the compound of formula Ib is isolated and purified bytechniques well known in the art, such as extraction techniques andsilica gel chromatography respectively. For example, the quenchedreaction is extracted with a suitable organic solvent, such as methylenechloride, the organic extracts are combined, dried over anhydrousmagnesium sulfate, filtered, and concentrated under vacuum to providecrude compound of formula Ib. This crude material is then purified bysilica gel chromatography with a suitable eluent, such as hexane/ethylacetate (1:1) to provide the purified compound of formula Ib.

Alternatively, the coupling reaction may be carried out using palladiumdiacetate with a suitable organic solvent, such as n-propanol oracetone. See for example, Organic Synthesis 1998, 75, 61; Goodson, F.E.; Wallow, T. I.; Novak, B. M. and Organic Synthesis 1998, 75, 53;Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. whereinanalogous coupling conditions are employed.

The boronic acid (6) may be prepared, for example, by reacting atrialkyl borate, such as triisopropyl borate with an appropriateorganolithium compound at reduced temperature. For example,2-fluorobenzeneboronic acid may be prepared by reacting2-fluorobromobenzene with butyllithium in tetrahydrofuran at about −78°C. to afford 2-fluorophenyl lithium, and then reacting thisorganolithium compound with triisopropyl borate. This is followed byhydrolysis with aqueous HCl.

The compounds of formulas Ic, Id, and Ie can be prepared as set forth inScheme III. The reagents and starting materials are readily available toone of ordinary skill in the art. All substituents, unless otherwisespecified are as previously defined.

In Scheme III, step A, the compound of formula Ib′ wherein z is 0 or aninteger 1, 2, 3 or 4, is reduced to the amine of formula Ic underconditions well known in the art. For example, see Jerry March,“Advanced Organic Chemistry,” second edition, McGraw-Hill Book Company,1977, page 835. More specifically, for example, compounds of formula Ib′are dissolved in a suitable organic solvent, such as tetrahydrofuran andtreated with an excess of a suitable reducing agent, such asborane-methyl sulfide complex. The reaction mixture is then heated atreflux for about 8 to 16 hours, and then allowed to cool to roomtemperature. The reaction is treated with a mixture oftetrahydrofuran/methanol (1:1) until foaming ceases. The reaction isthen treated with 5N aqueous sodium hydroxide and heated at reflux forabout 3 to 6 hours. The reaction is then cooled to room temperature andextracted with a suitable organic solvent, such as methylene chloride.The organic extracts are combined, dried over potassium carbonate,filtered, and concentrated under vacuum to provide the crude amine offormula Ic. The crude material is then purified by techniques well knownin the art, such as silica gel chromatography or formation of thecorresponding HCl salt and subsequent crystallization. For example, thecrude amine of formula Ic is dissolved in a suitable organic solvent,such as diethyl ether and treated with excess anhydrous HCl gas. Themixture is allowed to stir for about 1 to 3 hours and the resultingprecipitate is collected by filtration. The precipitate is washed withcold diethyl ether and dried under vacuum to provide the purified amineHCl salt of formula Ic.

In Scheme III, step B the amine of formula Ic is sulfonylated understandared conditions with a sulfonyl chloride of formula ClSO₂R¹⁵,wherein R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, to provide the compound of formulaId. For example, the amine of formula Ic is dissolved in a suitableorganic solvent, such as methylene chloride under an atmosphere ofnitrogen, and treated with an excess of a suitable organic base, such astriethylamine. The solution is cooled to about 0° C. and treated withabout 1.1 to about 1.5 equivalents of a sulfonyl chloride of formulaClSO₂R¹⁵. After addition is complete, the reaction mixture is allowed towarm to room temperature and stirred for about 8 to 16 hours. Thereaction is then quenched with water, the organic layer is separated,dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to provide the crude compound of formula Id. This crude materialis purified by silica gel chromatography with a suitable eluent, such asethyl acetate/hexane (1:1) to provide the purified compound of formulaId.

In Scheme III, step C the amine of formula Ic is converted to the amideof formula Ie under conditions well known in the art. For example, amideformation can be carried out using standard peptide coupling procedureswell known in the art, such as the azide method, the mixed carbonic acidanhydride (isobutyl chloroformate) method, or the carbodiimide(dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-solublecarbodiimide) method. Some of these methods, such as the carbodiimidemethod, can be enhanced by adding 1-hydroxybenzotriazole. Morespecifically, for example, the amine of formula Ic is dissolved in asuitable organic solvent, such as methylene chloride under an atmosphereof nitrogen, and treated with an excess of a suitable organic base, suchas triethylamine. The solution is cooled to about 0° C. and treated withabout 1.1 to about 1.5 equivalents of an acid chloride of formulaClCOR¹⁵. After addition, the reaction mixture is allowed to warm to roomtemperature and stirred for about 8 to 16 hours. The reaction is thenquenched with water and dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum to provide the crude amide of formula Ie.This crude material is purified by silica gel chromatography with asuitable eluent, such as ethyl acetate/hexane (1:1) to provide thepurified compound of formula Ie.

The following examples further illustrate the invention and representtypical syntheses of the compounds of formula I as described generallyabove. The reagents and starting materials are readily available to oneof ordinary skill in the art. As used herein the term “Chromatotron®”(Harrison Research Inc., 840 Moana Court, Palo Alto Calif. 94306) isrecognized by one of ordinary skill in the art as an instrument which isused to perform centrifugal thin-layer chromatography. As used herein,the following terms have the meanings indicated: “eq” refers toequivalents; “g” refers to grams; “mg” refers to milligrams; “L” refersto liters; “mL” refers to milliliters; “μL” refers to microliters; “mol”refers to moles; “mmol” refers to millimoles; “psi” refers to pounds persquare inch; “min” refers to minutes; “h” or “hr” refers to hours; “°C.” refers to degrees Celsius; “TLC” refers to thin layerchromatography; “HPLC” refers to high performance liquid chromatography;“R_(f)” refers to retention factor; “R_(t)” refers to retention time;“δ” refers to part per million down-field from tetramethylsilane; “THF”refers to tetrahydrofuran; “DMF” refers to N,N-dimethylformamide; “DMSO”refers to methyl sulfoxide; “LDA” refers to lithium diisopropylamide;“EtOAc” refers to ethyl acetate; “aq” refers to aqueous; “iPrOAc” refersto isopropyl acetate; “MTBE” refers to tert-butyl methyl ether; “methylDAST” refers to dimethylaminosulfur trifluoride, “DAST” refers todiethylaminosulfur trifluoride, “DBU” refers to1,8-diazabicyclo[5.4.0]undec-7-ene; as used herein “Pd(dppf)₂Cl₂catalyst” refers to([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexwith CH₂Cl₂; as used herein the terms “Me”, “Et”, “Pr”, “iPr”, and “Bu”refer to methyl, ethyl, propyl, isopropyl, and butyl respectively, and“RT” refers to room temperature.

EXAMPLE 1

Preparation of [2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine.

Preparation of Methyl 2-(4-bromophenoxy)propanoate.

Scheme I or II, step A: In a 3 L round-bottomed flask fitted with a stirbar, at room temperature, and under a nitrogen atmosphere, 4-bromophenol(50.0 g, 289 mmol) in 290 mL of N-N-dimethylformamide was added dropwiseto sodium hydride (7.6 g, 317 mmol) in 290 mL of N-N-dimethylformamide.After mixing for 45 minutes, 2-bromopropionate (47.0 g, 290 mmol) in 290mL of N-N-dimethylformamide was added dropwise from an addition funnel,and was followed with the addition of sodium iodide (52.0 g, 347 mmol,neat). The reaction mixture was then brought to reflux at 80° C. for 3hours. The reaction mixture was allowed to cool to room temperature,whereby it was diluted with 1.6 L H₂O, and extracted three times with500 mL of ethyl acetate. The organic layer was washed two times with 500mL of H₂O, dried with potassium carbonate, filtered, and concentratedunder reduced vacuum to yield 81.8 g of viscous brown oil. This crudematerial was purified via silica gel chromatography, employing aHewlett-Packard HPLC 2000 and eluting with a 1:1 hexane:ethyl acetatesolvent system to yield the intermediate title compound (37.0 g, 49%) asa viscous oil. Electrospray-MS 260, d (M*+1),Preparation of 2-(4-Bromophenoxy)propanamide.

Scheme I or II, step B: Methyl 2-(4-bromophenoxy)propanoate (37.01 g,143 mmol), ammonia (1.86 L of a 2M solution in methanol) andtetrahydrofuran (475 mL) were combined in a 3 L round bottom flask atroom temperature, under a nitrogen atmosphere, and stirred by stirbar,for 48 hours. Upon completion, the reaction mixture was concentratedunder reduced pressure to yield the intermediate title compound (35.9 g,100%) as a viscous oil. Electrospray-MS 245, d (M*+1).

Preparation of Final Title Compound.

Scheme I or II, steps C and D: In a 1000 mL 3-neck flask, fitted with athermometer, a stirbar and a condenser, 2-(4-bromophenoxy)propanamide(6.7 g, 27.4 mmol) was combined with borane-methyl sulfide complex (27.5mL of a 10 M concentration in excess methyl sulfide), andtetrahydrofuran (330 mL). The is reaction mixture was heated at refluxwith stirring, at 70° C., overnight, under a nitrogen atmosphere. Thereaction mixture was allowed to cool to room temperature and 82.4 mL of1:1 tetrahydrofuran methyl alcohol was added dropwise, slowly, untilfoaming ceased. Next, 5N sodium hydroxide (257 mL) was added, and thereaction mixture was refluxed for 5 hours. The mixture was thenpermitted to cool to room temperature and extracted three times with 200mL methylene chloride. The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated under reduced vacuum, yielding 5.3 gof viscous purple oil. This oil was dissolved in diethyl ether, andacidified with anhydrous hydrochloric acid gas (until precipitationoccurred). The acid mixture was allowed to stir at room temperature for1 hr, forming a white precipitate. The precipitate was captured byvacuum filtration yielding 4.4 g of white solid. The precipitate wasthen dissolved into methylene chloride (185 mL) and added totriethylamine (10 mL, 69 mmol) in a 500 mL 3-neck flask fitted with athermometer under a nitrogen atmosphere. The mixture was then cooled to0° C. and 2-propanesulfonyl chloride (5.0 mL, 41 mmol) was added bysyringe. The mixture was permitted to come to room temperature, andstirred overnight, under a nitrogen system. The reaction was quenchedwith excess water, and the organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated under vacuum, yielding 5.03 gviscous oil. Purification was conducted using a Hewlett-Packard HPLC2000, with two silica cartridges, and eluting with a 1:1 hexane:ethylacetate solvent system, yielding the final title compound (3.5 g, 38%)as a slow crystallizing, yellow viscous oil. Electrospray-MS 337, d(M*+1).

Analysis

-   Theory: C 42.87, H 5.40, N 4.16.-   Found: C 42.82, H 5.38, N 4.12.

EXAMPLE 1A

Preparation of[(2S)-2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine.

Preparation of (2S)-2-(4-bromophenoxy)propanoic acid.

Scheme II, step A: To a mixture of sodium hydride (54.92 g, 1.37 moles)and THF (500.0 ml) at reflux was added a solution of 4-bromophenol (47.6g, 0.275 moles) dissolved in THF (200.0 ml) over a period of 60.0minutes (vigorous gas evolution is observed which can be controlled bythe rate of substrate addition). The reaction is then heated at refluxuntil no gas evolution is observed. Then neat (S)α-chloropropionic acid(59.72 g, 0.550 moles) is added very carefully over a period of 60.0minutes (gas evolution can be controlled by the rate of addition). Thereaction is then heated at reflux for 120.0 minutes, then quenched withdeionized water (1000.0 ml) at reflux very carefully. The reaction isthen allowed to equilibrate to room temperature and the organicextracted with methylene chloride (1400.0 ml). To the aqueous layer,which contains the sodium salt of the product, is then added freshmethylene chloride (700.0 ml) and the mixture is acidified with 6N HCl(180.0 ml) very carefully at room temperature. The lower organic layeris then separated and subsequently dried with anhydrous magnesiumsulfate, filtered, and solvent exchanged with hexane under reducedpressure to to afford an off tan precipitate of the intermediate titlecompound, (65.06 g, 96.4%); ¹H nmr (CDCl₃) δ 1.65-1.66 (d, 3H, J=6.83Hz), 4.72-4.76 (m, 1H), 6.76-6.78 (d, 2H, J=9.03 Hz), 7.37-7.39 (d, 2H,J=9.03), 11.0; ¹³C nmr (CDCl₃) δ 18.61, 72.40, 114.43, 117.15, 132.75,156.57, 178.31).Preparation of (2S)-2-(4-bromophenoxy)propanamide.

Scheme II, step B: To a solution of (2S)-2-(4-bromophenoxy)propanoicacid (prepared above) and THF (300.0 ml) at room temperature was added(N-methylmorholine) NMM (11.02 ml) immediately followed by(Chlorodimethoxytriazine) CDMT (17.6 g). After 45 minutes of stirring,NMM (17.64 ml) and ammonium chloride (8.04 g) was added to the reactionmixture. The reaction was then capped and stirred for 24.0 hours.Filtration of the precipitated solid and concentration of the filtrateunder reduced pressure afforded an oil. To the oil was then addedmethylene chloride (150.0 ml) and 1N HCl (200.0 ml) with vigorousstirring. The organic layer was then separated, dried with anhydrousmagnesium sulfate, filtered, and subsequently solvent exchanged withhexane to afford a tan precipitate. The precipitate was then dried in ahouse vacuum at 50° C. to provide the intermediate title compound (18.93g, 77.4%); ¹H nmr (CDCl₃) δ 1.56-1.58 (d, 3H, J=6.83Hz), 4.6 (m, 1H),5.58 (b, 1H), 6.47 (b, 1H), 6.78-6.81 (d, 2H, J=9.03 Hz), 7.40-7.42 (d,2H, J=9.03 Hz).Preparation of (2S)-2-(4-bromophenoxy)propylamine.

Scheme II, step C: To a solution of (2S)-2-(4-bromophenoxy)propanamide(18.93 g, 77.93 mmoles) and THF (300.0 ml) at room temperature was added10M solution of borane dimethylsufide (23.42 ml, 233.8 mmoles) over aperiod of 20 minutes. The reaction exothermed with evolution of gas. Itwas heated at reflux for 4.5 hours then quenched very carefully with 4NHCl in Dioxane solution over a period of 30.0 minutes (caution:evolution of gas). The reaction was stirred for 10.0 minutes, thenethanol (105.7 ml) was added very carefully over a period of 30.0minutes. The reaction was concentrated to a constant weight of a whiteslurry (54.0 g). To the slurry was then added toluene (200.0 ml)followed by azeotropic removal of low boiling solvents to a whiteslurry, followed by addition of ethyl acetate (100.0 ml) and ethyl ether(100.0 ml). Vigorous stirring of the reaction mixture, filtration, andsubsequent drying under a house vacuum at 45° C. for 18.0 hours affordedthe intermediate title compound (13.0 g, 63%) as a white precipitate; ¹Hnmr (DMSO) δ 1.21-1.22 (d, 3H, J=6.1 Hz), 2.90-2.98 (m, 1H), 3.03-3.05(m, 1H), 4.67-4.70 (m, 1H), 6.96-6.98 (d, 2H, J=9.03 Hz), 7.43-7.45 (d,2H, J=9.03 Hz); 13C nmr (DMSO) δ 17.48, 43.75, 71.63, 113.37, 119.26,132.88, 156.82).

Preparation of Final Title Compound.

Scheme II, step D: To a reaction mixture of(2S)-2-(4-bromophenoxy)propylamine (19.0 g, 71.275 mmoles) and methylenechloride (200.0 ml) at room temperature was added 2N NaOH (150.0 ml) allat once with vigorous stirring for 45 minutes. The organic layer wasseparated, dried anhydrous magnesium sulfate, filtered, and the filtrateconcentrated to an oil (16.22 g). To a solution of this oil in methylenechloride (225.0 ml) at room temperature was then added triethylamine(23.6 ml, 169.23 mmol) and N,N-dimethylaminopyridine (0.43 g) withstirring. The solution was cooled to −20° C. with dry ice/acetone bath,and a solution of isopropylsulfonyl chloride (9.5 ml, 84.62 mmol)dissolved in methylene chloride (25 ml) was added over a period of 30minutes while maintaining the temperature at −20° C. The reaction wasthen stirred to room temperature overnight. The reaction was monitoredwith TLC (1:1 ethylacetate/hexane) until the reaction was complete. Thereaction was quenched with 3N HCl solution (100.0 ml), the organic layerseparated then dried with anhydrous magnesium sulfate. Subsequentfiltration and concentration at reduced pressure afforded the finaltitle compound (23.7 g, 100%) as an oil; ¹H nmr (CDCl₃) δ 1.25-1.26 (d,3H, J=6.35 Hz), 1.33-1.35 (d, 6H, J=6.83 Hz), 3.14-3.19 (m, 1H),3.22-3.26 (m, 1H), 3.34-3.36 (m, 1H), 4.43-4.46 (m, 1H), 4.74-4.76 (m,NH), 6.77-6.79 (d, 2H, J=9.03 Hz), 7.35-7.37 (d, 2H, J=9.03 Hz); ¹³C nmr(CDCl₃) δ 16.91, 48.59, 53.94, 74.13, 113.84, 118.09, 132.72, 156.51).

EXAMPLE 1B

Preparation of[(2R)-2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine.

The title compound can be prepared from (R)-2-chloroproprionic acid in amanner analogous to the the procedure set forth in example 1A.

EXAMPLE 2

Preparation of[(Methylethyl)sulfonyl]{2-[4-(4-(3-thienyl)phenoxy]propyl}amine.

Scheme II, step E:[2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (260 mg, 0.773mmol, prepared in example 1), thiophene-3-boronic acid (120 mg, 0.938mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol),sodium carbonate (276 mg in 1.3 mL water) and 1,4-dioxane (5 mL) werecombined in a 15 mL round bottom flask, fitted with a condenser,stirbar, and in a temperature regulated oil bath. The reaction mixturewas heated at reflux (70° C.) under a nitrogen atmosphere overnight. Thereaction was quenched with water, extracted three times with 25 mL ofmethylene chloride, and the organic layer dried with anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure, yielding 230mg brown viscous oil. This material was purified via silica gelchromatography, utilizing a Chromatotron® (the Chromatotron® isavailable from Harrison Research Inc., 840 Moana Court, Palo Alto Calif.94306) with a 2000 μm rotor utilizing an eluent of 1:1 hexane:ethylacetate, yielding the title compound (126 mg, 48.4%), Electrospray-MS340.0 (M*+1).

Analysis

-   Theory: C 56.61, H 6.24, N 4.13.-   Found: C 56.41, H 6.12, N 4.11.

EXAMPLE 3

Preparation of{2-[4-(3-Aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (230 mg, 82%) was prepared from[2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (270 mg, 0.803mmol, prepared in example 1), 3-aminobenzeneboronic acid monohydrate(150 mg, 0.968 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg,0.004 mmol), 2 M sodium carbonate (290 mg in 1.4 mL water) and1,4-dioxane (5.5 mL) in a manner analogous to the procedure described inExample 2.

Electrospray-MS 347.2 (M*−1).

EXAMPLE 4

Prepation of [(Methylethyl)sulfonyl][2-(4-phenylphenoxy)propyl]amine.

Scheme II, step E: The title compound (290 mg, 48.4%) was prepared from[2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (450 mg, 1.34mmol, prepared in example 1), benzeneboronic acid (200 mg, 1.64 mmol),tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.007 mmol), 2 Msodium carbonate (480 mg in 2.3 mL water) and 1,4-dioxane (9 mL) in amanner analogous to the procedure described in Example 2.

Electrospray-MS 334.0 (M*+1).

EXAMPLE 5

Preparation of{2-[4-(2-Chlorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (125 mg, 38%) was prepared from[2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.89mmol, prepared in example 1), 2-chlorobenzeneboronic acid (170 mg, 1.09mmol), tetrakis(triphenylphosphine)palladium(0) (5.6 mg, 0.005 mmol), 2M sodium carbonate (320 mg in 1.5 mL water) and 1,4-dioxane (9 mL) in amanner analogous to the procedure described in Example 2.

Electrospray-MS 368.0 (M*+1).

EXAMPLE 6

Preparation of[(Methylethyl)sulfonyl]{2-[4-(3-methylphenyl)phenoxy]propyl}amine.

Scheme II, step E: The title compound (18 mg, 6%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(275 mg, 0.818 mmol, prepared in example 1), 3-methylbenzeneboronic acid(135 mg, 0.993 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg,0.013 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water) and1,4-dioxane (5.5 mL) was prepared in a manner analogous to the proceduredescribed in Example 2. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 110 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase, chromatography on a Vydac C-18 column in a gradient of 5to 70% of 0.1% trifluoroacetic acidlacetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 348.0 (M*+1).

EXAMPLE 7

Preparation of{2-[4-(4-Chlorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (10.9 mg, 3.2%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(270 mg, 0.803 mmol, prepared in example 1), 4-chlorobenzeneboronic acid(151 mg, 0.966 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg,0.013 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water) and1,4-dioxane (5.5 mL) in a manner analogous to the procedure described inExample 2. The crude material was purified utilizing a Chromatotron®with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system,yielding 115 mg of a co-eluting mixture of unreacted starting materialand title compound. This mixture was further purified by reverse phasechromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1%trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/minelution rate.

Electrospray-MS 369.0 (M*+1).

EXAMPLE 8

Preparation of{2-[4-(3-Chlorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E:[2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.892mmol, prepared in example 1), 3-chlorobenzeneboronic acid (170 mg, 1.09mmol), dichlorobis(triphenylphosphine)palladium(II) (25 mg, 0.036 mmol),2 M sodium carbonate (320 mg in 1.5 mL water) and 1,2-dimethoxyethane(6.0 mL) were combined in a 15 ml round bottom flask, fitted with acondenser, stirbar, and in a temperature regulated oil bath, and heatedat reflux 85 C. in a nitrogen system overnight. The reaction mixture wasquenched with water and extracted three times with 25 mL of methylenechloride. The organic extracts were combined, dried over anyhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure,yielding 190 mg brown viscous oil. This material was purified via silicagel chromatography, utilizing a Chromatotron® with a 2000 μm rotor in a1:1 hexane:ethyl acetate solvent system, yielding the title compound(175 mg, 53%) as a yellow foam. Electrospray-MS 369.0 (M*+1).

EXAMPLE 9

Preparation of[(Methylethyl)sulfonyl]{2-[4-(2-methylphenyl)phenoxy]propyl}amine.

Scheme II, step E: The title compound (120 mg, 34%, yellow foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(343 mg, 1.02 mmol, prepared in example 1), 2-methylbenzeneboronic acid(165 mg, 1.21 mmol), dichlorobis(triphenylphosphine)palladium(II) (30mg, 0.043 mmol), 2 M sodium carbonate (370 mg in 1.75 mL water), and1,2-dimethoxyethane (6.8 mL) in a manner analogous to the proceduredescribed in Example 8.

Electrospray-MS 348.0 (M*+1).

EXAMPLE 10

Preparation of[(Methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxy]propyl}amine.

Scheme II, step E: The title compound (243 mg, 77.6%, yellow foam) wasprepared from [2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine(310 mg, 0.922 mmol, prepared in example 1), 3-(2-thienyl)benzeneboronicacid (145 mg, 1.13 mmol), dichlorobis(triphenylphosphine)palladium(II)(26 mg, 0.037 mmol), 2 M sodium carbonate (335 mg in 1.6 mL water), and1,2-dimethoxyethane (6 mL) in a manner analogous to the proceduredescribed in Example 8.

Electrospray-MS 340.0 (M*+1). The compound of example 10 has beenspecifically excluded from the scope of the present invention.

EXAMPLE 11

Preparation of[(Methylethyl)sulfonyl]{2-[4-(4-(2-thienyl)phenyl)phenoxy]propyl}amine.

Scheme II, step E: The title compound (145 mg, 54%, yellow foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(265 mg, 0.788 mmol, prepared in example 1), 2-thienylboronic acid (125mg, 0.946 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg,0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and1,2-dimethoxyethane (5.25 mL) in a manner analogous to the proceduredescribed in Example 8.

Electrospray-MS 340.0 (M*+1).

EXAMPLE 12

Preparation of4-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzaldehyde.

Scheme II, step E: The title compound (82 mg, 30%, yellow foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(252 mg, 0.749 mmol, prepared in example 1), 4-formylbenzeneboronic acid(135 mg, 0.900 mmol), dichlorobis(triphenylphosphine)palladium(II) (21mg, 0.030 mmol), 2 M sodium carbonate (270 mg in 1.3 mL water), and1,2-dimethoxyethane (5 mL) in a manner analogous to the proceduredescribed in Example 8.

Electrospray-MS 362.0 (M*+1).

EXAMPLE 13

Preparation of[2-(4-(2H-Benzo[3,4-d]1,3-dioxolan-5-yl)phenoxy)propyl][(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (68 mg, 24%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(250 mg, 0.7435 mmol, prepared in example 1),3,4-methylenedioxybenzeneboronic acid (150 mg, 0.904 mmol),dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.030 mmol), 2 Msodium carbonate (270 mg in 1.3 mL water), and 1,2-dimethoxyethane (5mL) in a manner analogous to the procedure described in Example 8. Thecrude material was purified utilizing a Chromatotron® with a 2000 μmrotor in a 1:1 hexane:ethyl acetate solvent system, yielding 140 mg of aco-eluting mixture of unreacted starting material and title compound.This mixture was further purified by reverse phase chromatography on aVydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroaceticacid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.

Electrospray-MS 378.0 (M*+1).

EXAMPLE 14

Preparation of[(Methylethyl)sulfonyl]{2-[4-(4-methylphenyl)phenoxy]propyl}amine.

Scheme II, step E: The title compound (40 mg, 16%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(239 mg, 0.711 mmol, prepared in example 1), 4-methylbenzeneboronic acid(116 mg, 0.853 mmol), dichlorobis(triphenylphosphine)palladium(II) (20mg, 0.028 mmol), 2 M sodium carbonate (255 mg in 1.2 mL water), and1,2-dimethoxyethane (4.75 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 207 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified is byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 348.0 (M*+1).

EXAMPLE 15

Preparation of3-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzaldehyde.

Scheme II, step E: The title compound (130 mg, 46%, yellow foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(265 mg, 0.788 mmol, prepared in example 1), 3-formylbenzeneboronic acid(160 mg, 0.964 mmol), dichlorobis(triphenylphosphine)palladium(II) (22mg, 0.031 mmol), 2 M sodium carbonate (285 mg in 1.35 mL water), and1,2-dimethoxyethane (5.25 mL) in a manner analogous to the proceduredescribed in Example 8.

Electrospray-MS 362.0 (M*+1).

EXAMPLE 16

Preparation of[(Methylethyl)sulfonyl](2-{4-[3-(trifluoromethyl)phenyl]phenoxy}propyl)amine.

Scheme II, step E: The title compound (44 mg, 15%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(240 mg, 0.714 mmol, prepared in example 1),3-trifluoromethylbenzeneboronic acid (162 mg, 0.853 mmol),dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), 2 Msodium carbonate (255 mg in 1.2 mL water), and 1,2-dimethoxyethane (4.75mL) in a manner analogous to the procedure described in Example 8. Thecrude material was purified utilizing a Chromatotron® with a 2000 μmrotor in a 1:1 hexane:ethyl acetate solvent system, yielding 192 mg of aco-eluting mixture of unreacted starting material and title compound.This mixture was further purified by reverse phase chromatography on aVydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroaceticacid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.

Electrospray-MS 402.0 (M*+1).

EXAMPLE 17

Preparation of2-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzaldehyde.

Scheme II, step E: The title compound (68 mg, 21%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(300 mg, 0.892 mmol, prepared in example 1), 2-formylbenzeneboronic acid(180 mg, 1.085 mmol), dichlorobis(triphenylphosphine)palladium(II) (25mg, 0.036 mmol), 2 M sodium carbonate (320 mg in 1.5 mL water), and1,2-dimethoxyethane (6 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 280 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 362.0 (M*+1).

EXAMPLE 18

Preparation of[(Methylethyl)sulfonyl](2-{4-[4-(trifluoromethyl)phenyl]phenoxy}propyl)amine.

Scheme II, step E: The title compound (68 mg, 21.5%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(267 mg, 0.794 mmol, prepared in example 1),4-trifluoromethylbenzeneboronic acid (180 mg, 0.948 mmol),dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 Msodium carbonate (285 mg in 1.35 mL water), and 1,2-dimethoxyethane(5.25 mL) in a manner analogous to the procedure described in Example 8.The crude material was purified utilizing a Chromatotron® with a 2000 μmrotor in a 1:1 hexane:ethyl acetate solvent system, yielding 190 mg of aco-eluting mixture of unreacted starting material and title compound.This mixture was further purified by reverse phase chromatography on aVydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroaceticacid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.

Electrospray-MS 402.0 (M*+1).

EXAMPLE 19

Preparation of{2-[4-(4-Methoxyphenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (34 mg, 14%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(225 mg, 0.669 mmol, prepared in example 1), 4-methoxybenzeneboronicacid (125 mg, 0.822 mmol), dichlorobis(triphenylphosphine)palladium(II)(20 mg, 0.028 mmol), 2 M sodium carbonate (245 mg in 1.15 mL water), and1,2-dimethoxyethane (4.5 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 220 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 364.0 (M*+1).

EXAMPLE 20

Preparation of{2-[4-(2-Fluorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (50 mg, 18%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(260 mg, 0.773 mmol, prepared in example 1), 2-fluorobenzeneboronic acid(130 mg, 0.929 mmol), dichlorobis(triphenylphosphine)palladium(II) (22mg, 0.031 mmol), 2 M sodium carbonate (280 mg in 1.3 mL water), and1,2-dimethoxyethane (5.2 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 230 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 352.0 (M*+1).

EXAMPLE 21

Preparation of{2-[4-(4-Fluorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (60 mg, 21%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(275 mg, 0.818 mmol, prepared in example 1), 4-fluorobenzeneboronic acid(140 mg, 1.001 mmol), dichlorobis(triphenylphosphine)palladium(II) (23mg, 0.033 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water), and1,2-dimethoxyethane (5.5 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 310 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 352.0 (M*+1).

EXAMPLE 22

Preparation of{2-[4-(3-Methoxyphenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (110 mg, 35%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(290 mg, 0.862 mmol, prepared in example 1), 3-methoxybenzeneboronicacid (160 mg, 1.053 mmol), dichlorobis(triphenylphosphine)palladium(II)(25 mg, 0.036 mmol), 2 M sodium carbonate (310 mg in 1.5 mL water), and1,2-dimethoxyethane (5.75 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 350 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 364.0 (M*+1).

EXAMPLE 23

Preparation of{2-[4-(3-Fluorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Scheme II, step E: The title compound (85 mg, 30%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(275 mg, 0.818 mmol, prepared in example 1), 3-fluorobenzeneboronic acid(140 mg, 1.001 mmol), dichlorobis(triphenylphosphine)palladium(II) (23mg, 0.033 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water), and1,2-dimethoxyethane (5.5 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 270 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 352.0 (M*+1).

EXAMPLE 24

Preparation of[(Methylethyl)sulfonyl](2-{4-[2-(trifluoromethyl)phenyl]phenoxy}propyl)amine.

Scheme II, step E: The title compound (75 mg, 17%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(375 mg, 1.115 mmol, prepared in example 1), 3-fluorobenzeneboronic acid(255 mg, 1.343 mmol), dichlorobis(triphenylphosphine)palladium(II) (32mg, 0.046 mmol), 2 M sodium carbonate (400 mg in 1.9 mL water), and1,2-dimethoxyethane (7.5 mL) in a manner analogous to the proceduredescribed in Example 8. The crude material was purified utilizing aChromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solventsystem, yielding 270 mg of a co-eluting mixture of unreacted startingmaterial and title compound. This mixture was further purified byreverse phase chromatography on a Vydac C-18 column on a gradient of 5to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45minutes at 200 mL/min elution rate.

Electrospray-MS 402.0 (M*+1).

EXAMPLE 25

Preparation of{2-[4-(4-Cyanophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine.

Preparation of 4-Cyanobenzeneboronic Acid.

Following a modified literature procedure of Perria, G. J.; et al., J.Am. Chem. Soc., 118, 10220-10227 (1996), a solution of4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in thepresence of activated 3 Å molecular sieves at room temp. This solutionwas filtered and cooled to −100° C. Next, 1.6 M solution ofn-butyllithium in hexanes (355 mL; 0.567 mol) was added to the coldsolution over 15 min while maintaining the internal temperature between−105 and −93° C. To the resulting orange reaction mixturetrimethylborate (81 g, 0.78 mol) was added over 3 min, brieflyincreasing the reaction temperature to −72° C. The reaction mixture wasre-cooled to −100° C. over 5 min and then was allowed to warm slowly toroom temperature over 2.3 h. The reaction mixture was acidified with 4NHCl to pH 2.2 and was diluted with CH₂Cl₂ (200 mL). The aqueous layerwas separated and the organic layer was washed with brine (2×200 mL),dried (MgSO₄), filtered, and reduced under pressure to give a paleyellow solid. This solid was additionally purified by dissolution in 1NNaOH and extraction into CH₂Cl₂/THF (1:1, 2×200 mL). The aqueous phasewas acidified with 4N HCl to pH 2.2 and was extracted into CH₂Cl₂/THF(1:1, 500 mL). The combined organic extracts were concentrated to acrude solid (64.6 g) that was triturated with diethyl ether (160 mL) anddried under vacuum to afford the intermediate title compound (44.0 g,59.9%) as a white powder.

¹H NMR (d₆-acetone, 300 MHz): δ 8.03 (d, 2H, J=8.1), 7.75 (d, 2H,J=8.4), 7.54 (s, 2H).

Preparation of Final Title Compound.

Scheme II, step E: The final title compound (128 mg, 60%) was preparedfrom [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (200 mg,0.595 mmol, prepared in example 1), 4-cyanobenzeneboronic acid (105 mg,0.715 mmol), tetrakis(triphenylphosphine)palladium(0) (3.7 mg, 0.003mmol), 2 M sodium carbonate (212 mg in 1 mL water) and 1,4-dioxane (4mL) in a manner analogous to the procedure described in Example 2. It isunderstood that the final title compound name for example 25 above,{2-[4-(4-cyanophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine, isequivalent to the alternative name of4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile.

Electrospray-MS 359.0 (M*+1).

Analysis

-   Theory: C 63.66, H 6.19, N 7.82.-   Found: C 63.67, H 5.84, N 8.00.

EXAMPLE 25A

Preparation of4-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile.

Preparation of (2R)-2-(4-bromophenoxy)propanamide:

and preparation of (2S)-2-(4-bromophenoxy)propanamide.

2-(4-Bromophenoxy)propanamide (prepared in example 1) is separated intothe (2R)-2-(4-bromophenoxy)propanamide and(2S)-2-(4-bromophenoxy)propanamide enantiomers using standard techniqueswell known in the art. For example, 2-(4-bromophenoxy)propanamide can beseparated into the corresponding enantiomers using chiral chromatographyon a Chiralcel OD® column (Chiral Technologies, Inc., 730 SpringdaleDrive, Exton, Pa. 19341, 4.6×250 mm) with an eluent of 20%isopropanol/heptane at a flow rate of 1 mL/min.

Elemental Analysis for (2S)-2-(4-bromophenoxy)propanamide.

-   C(Theory): 44.2872 C(Found): 41.17-   H(Theory): 4.1295 H(Found): 4.02-   N(Theory): 5.7383 N(Found): 5.72    Elemental Analysis for (2R)-2-(4-bromophenoxy)propanamide.-   C(Theory): 44.2872 C(Found): 44.51-   H(Theory): 4.1295 H(Found): 4.21-   N(Theory): 5.7383 N(Found): 5.60    Preparation of    [(2R-2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine.

Scheme II, steps C and D: (2R)-2-(4-bromophenoxy)propanamide (4.0 g,16.4 mmol), borane dimethylsulfide reagent (16.4 mL, 164 mmol), and THF(196 mL) were combined in a 2000 mL 3-neck round bottomed flask, affixedwith a thermometer, condenser, and rubber stopper. Under a nitrogenatmosphere, with stirring, the reaction mixture was refluxed at 70° C.overnight. When the reaction was complete by TLC, it was cooled toambient temperature. THF:methanol (49.2 mL, 1:1) was added by syringe,and when foaming ceased, 5N NaOH added by syringe. The reaction mixturewas heated at 55° C. for an additional five hours, monitoringoccasionally to determine if the borane complexes had been thoroughlybroken up. Upon completion, the reaction mixture was cooled to roomtemperature, and extracted three times with methylene chloride. Theorganic layer was dried with sodium sulfate, filtered, and concentratedunder reduced pressure, yielding 5.88 g of a viscous yellow oil. Thisoil was dissolved into 200 mL of diethyl ether, and acidified withconcentrated HCl gas, to pH<2. The acidic solution was stirred at RT forone hour, then vacuum filtered off white precipitate. The precipitatewas heated under vacuum for two hours at 40° C., yielding 2.85 g whitesolid. This solid was dissolved in methylene chloride 110 mL) in a 500mL 3-neck round bottomed flask, fitted with a thermometer, rubberstopper, and under a nitrogen system. The reaction mixture was thencooled to 0° C., triethylamine (5.7 mL, 41.0 mmol) and isopropylsulfonylchloride (2.76 mL, 24.6 mmol) respectively, were added by syringe andstirred overnight monitored until complete. The reaction was monitoredby TLC until complete. The reaction was then quenched with 200 mL water,and the layers were separated. The organic layer was washed with water,dried with sodium sulfate, filtered, and concentrated under reducedpressure yielding 4.16 g viscous brown oil. The product was furtherpurified by chromatography on a waters Prep 2000 using two Prep-Paks, ina 50:50 is hexanes:ethyl acetate solvent system. This yielded theintermediate title compound (2.81 g, 51%) as a slow crystallizingviscous brown oil.

Preparation of final title compound,4-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile.

Scheme II, step E: 4-Cyanobenzeneboronic acid (171 mg, 1.16 mmol,prepared in example 25), tetrakis(triphenylphosphine)palladium(0) (69mg, 0.063 mmol), 2 M sodium carbonate (1.6 mL), and[(2R)-2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (310 mg,0.922 mmol) were combined in a 15 mL round bottomed flask withdimethylethylene glycol (6.15 mL, DME), fitted with a condenser,stirbar, and in a temperature regulated oil bath, and refluxed in anitrogen system to 85° C., overnight. The reaction was allowed to coolto room temperature, and quenched with 15 mL of water, and extractedthree times with 15 mL ethyl acetate. The organic layer was dried withmagnesium sulfate, filtered through Celite®, and concentrated underreduced pressure, yielding 470 mg viscous black oil. This material wasfurther purified using a 4000 uM rotor on a Chromatotron® in a 1:1hexanes:ethyl acetate solvent system yielding the final title compound(57.5 mg, 18%) as white crystals.

MS-ES M*+1 (359.5).

Elemental Analysis:

-   C(Theory): 63.66 C(Found): 62.81-   H(Theory): 6.19 H(Found): 5.99-   N(Theory): 7.81 N(Found): 7.73

EXAMPLE 25B

Preparation of4-[4-((1S)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile.

The title compound is prepared in a manner analogous to the procedureset forth in example 25A from (2S)-2-(4-bromophenoxy)propanamide(prepared in exampel 25A).

EXAMPLE 26

Preparation of2-{4-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethanenitrile.

Preparation of 4-(cyanomethyl-phenylboronic acid, pinacol ester.

Using the method of Murata, M., et al., Y. J. Org. Chem, 62 6458-6459(1997), 4-iodophenylacetonitrile (23.9 g, 0.100 mol), Et₃N (42 mL, 0.30mol), acetonitrile (400 mL) and Pd(dppf)₂Cl₂ catalyst([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexwith CH₂Cl₂) were combined in a 1 L flask and the resulting solution wasevacuated and purged with nitrogen three times. The pinacolborane (22mL, 0.15 mol) was added and the mixture was heated at reflux for 3 h. ¹HNMR analysis of an aliquot indicated complete consumption of starting4-iodophenylacetonitrile. The mixture was cooled to room temperature,concentrated to an oil and taken up in CH₂Cl₂. This solution wasextracted with 0.1 N HCl (3×100 mL) and the organic phase was separated,concentrated and re-dissolved in methyl tert-butyl ether (MTBE). TheMTBE solution was passed through a filter packed with silica gel (300g). The eluant was concentrated to a dark red oil. This oil wasextracted with hexanes (500 mL) and the soluble fraction was decantedaway from a black oil (5 g). MTBE (5 mL) was added to this oil to give asuspension that was filtered through Celite®. This filtrated wascombined with the hexanes fraction and the solution was concentrated toan oil. Finally, the oil was re-dissolved in di-isopropyl ether (150 mL)and was diluted with hexanes (400 mL). This mixture was allowed to standfor 2 h, and then filtered to remove a dark precipitate. The resultingamber filtrate was concentrated to an oil, re-dissolved in hexanes (400mL) and concentrated to 75 mL without added heat. This treatmentresulted in the precipitation of the desired intermediate title compoundas a golden waxy solid that was air-dried to afford 23.0 g (96.2%):

¹H NMR (CDCl₃, 300 MHz): δ 7.8 (d, 2H); 7.35 (d, 2H); 3.8 (s, 2H) 1.15(s, 12H).

Preparation of 4-(cyanomethyl)-phenylboronic acid.

Using the method of Coutts, S. J., et al., Tetrahedron Lett., 35,5109-5112 (1994), 4-(cyanomethyl)-phenylboronic acid, pinacol ester(25.0 g, 0.103 mol) was dissolved in acetone (500 mL) and water (27 mL).To this solution, 1N aqueous ammonium acetate was added (256 mL),followed by NaIO₄ (66.9 g, 0.300 mol). The turbid mixture was stirredunder nitrogen for 2 h at room temperature to afford a thickersuspension. The reaction mixture was filtered and the filter cake waswashed with acetone (3×30 mL) and water (1×50 mL). The filtrated wasconcentrated to a solid that was suspended in water (30 mL) andfiltered. The filtrate was discarded. The combined collected solids wereslurried in acetone (200 mL) and filtered. The filtrate was concentratedand the residue was dissolved in acetone (100 mL). A small amount ofacetone-insoluble material was removed by filtration. The combinedfiltrates were concentrated to provide the intermediate title compound(18.9 g, 114%).

¹H NMR (d₆-acetone, 300 MHz) revealed the presence of H₂O in this lot: δ7.90 (d, 2H, J=8.1), 7.38 (d, 2H, J=8.1), 7.25 (br, s, 2H), 3.97 (s,2H).

Preparation of Final Title Compound.

Scheme II, step E: The final title compound (80 mg, 48%) was preparedfrom [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (150 mg,0.446 mmol, prepared in example 1), 4-(cyanomethyl)-phenylboronic acid(197 mg, 1.502 mmol), tetrakis(triphenylphosphine)palladium(0) (3.0 mg,0.003 mmol), 2 M sodium carbonate (212 mg in 1 mL water) and 1,4-dioxane(4 mL) in a manner analogous to the procedure described in Example 2.

Electrospray-MS 373.0 (M*+1).

Analysis

-   Theory: C 64.49, H 6.49, N 7.52.-   Found: C 64.65, H 6.08, N 7.56.

EXAMPLE 27

Preparation of[(Methylethyl)sulfonyl][2-(4-{3-[(methylsulfonyl)amino]phenyl}phenoxy)propyl]amine.

Preparation of benzotriazolyl methylsulfonate.

The intermediate title compound was prepared following a procedureadapted from Tet. Lett., 40 (1), 117 (1999). To a slurry ofhydroxybenztriazole hydrate (10.0 g, 74.0 mmoles) in methylene chloride(100 mL) was added triethylamine (15.0 g, 148 mmoles) followed by amethylene chloride rinse (4-5 mL). The solution was cooled to 4° C. anda solution of methanesulfonyl chloride (8.48 g, 74.0 mmoles) inmethylene chloride (25 mL) was added dropwise with stirring. HPLCanalysis revealed 78.9% hydroxybenztriazole and 21.1% benzotriazolylmethylsulfonate (relative area percent). An additional portion oftriethylamine (7.0 g, 69.2 mmoles) was introduced to the reactionvessel, followed by additional solution of methanesulfonyl chloride(8.48 g, 74.0 mmoles) in methylene chloride (25 mL) added dropwise at 8°C. HPLC analysis revealed 9% hydroxybenztriazole and 85% benzotriazolylmethylsulfonate (relative area percent).

The reaction mixture was allowed to warm to room temperature and thenwas suction filtered through a silica gel plug (20 g) capped withCelite. The solid filtration media was rinsed with fresh methylenechloride (2×100 mL). The filtrate was concentrated to a yellow paste(38.8 g) under reduced pressure. The crude paste was partitioned betweenMTBE (200 mL) and water (150 mL) to form a clear, two phase mixture. Theorganic phase was separated and extracted with water (2×150 mL). Theorganic phase was dried (Na₂SO₄), filtered, and the filtrate wasconcentrated, under vacuum, to afford 12.2 g of a yellow oil thatspontaneously solidified to a yellow solid.

Recrystallization of this solid was accomplished by dissolution in warmMTBE (50 mL), followed by the slow addition of heptanes (50 mL),stirring and slow cooling to room temperature. The mixture was stirredfor an additional 15-20 min and was suction filtered at room temperatureand the solid was rinsed with heptanes (5×). The solids were suctiondried to afford 9.04 g (57.3%) of benzotriazolyl methylsulfonate as awhite solid. The filtrate was refiltered and the 2^(nd) crop was rinsed2× with heptane. The additional solids were collected to obtain 0.46 gof additional white solid of benzotriazolyl methylsulfonate for a totalyield of (9.5 g, 62.5%). ¹H NMR (300 MHz, CDCl₃) δ 8.1 (d, 1H), 7.4-7.7(m, 3H), 3.6 (s, 3H).Preparation of 3-(amino)-phenylboronic acid, pinacol ester

3-Aminophenylboronic acid hydrate 97% (4.48 g, 0.029 mol) and pinacol(3.42 g, 0.030 mol) in methylene chloride (50 mL) were stirred for 17 h.HPLC analysis at 17 h revealed some unreacted boronic acid. After 2 daysof stirring at room temperature the reaction was shown to be complete(HPLC). The reaction mixture was extracted with 10% K₂CO₃ (2×50 mL) andthe organic phase was separated and dried (Na₂SO₄). After filtration,the organic phase was concentrated under reduced pressure to afford 4.41g (71.7%) of 3-(amino)-phenylboronic acid, pinacol ester as tan powder.¹H NMR (CDCl₃, 300 MHz): δ 7.10-7.24 (3H, m), 6.79 (1H, ddd, J=1.8, 2.7,7.2), 3.62 (2H, brs), 1.34 (12H, s).Preparation of 3-[(methylsulfonyl)amino]phenylboronic acid, pinacolester.

A solution of 3-(amino)-phenylboronic acid, pinacol ester (5.00 g, 22.8mmoles) and benzotriazolyl methyl (5.35 g, 25.1 mmoles) in DMF (50 mL)was heated to 50° C. with stirring under nitrogen. The reaction wasfollowed by HPLC. Complete conversion of aniline to sulfonamide wasobserved after 44 h of reaction. The mixture was allowed to cool and wasdiluted with MTBE (250 mL) and water (100 mL). The heterogeneous mixturewas shaken well and allowed to separate. The organic phase was isolatedand extracted with water (2×100 mL), 10% K₂CO₃ (1×100 mL) and again withwater (1×100 mL). The organic phase was isolated, dried (Na₂SO₄),filtered, and concentrated to afford 0.78 g of a mixture of mono and bissulfonamides as a brown oil.

The desired 3-[(methylsulfonyl)amino]phenylboronic acid, pinacol esterwas recovered from the alkaline aqueous layer, by cooling the 10% K₂CO₃washings (0° C.) and acidifying with the dropwise addition ofconcentrated sulfuric acid with stirring until a white precipitate wasobserved. The mixture was stirred cold for an additional 0.5 h and thensuction filtered, the solids rinsed with water (3×) and air-driedovernight to afford 1.06 g (16%) of pure3-[(methylsulfonyl)amino]phenylboronic acid, pinacol ester as a whitesolid.

Alternative preparation of 3-[(methylsulfonyl)amino]phenylboronic acid,pinacol ester.

3-(amino)-Phenylboronic acid, pinacol ester (54.6 g, 249 mmoles) wasdissolved in methylene chloride (250 mL) and treated with activated 3Asieves (26 g). This mixture was gravity filtered into a 2L round bottomflask and rinsed in with additional methylene chloride (250 mL).Triethylamine (50.4 g, 498 mmoles) was added to the reaction vessel withstirring at room temperature followed by a methylene chloride rinse (100mL). The reaction mixture was is cooled to 1-2° C. with stirring undernitrogen and a solution of methanesulfonyl chloride (28.3 g, 247mmoles)in methylene chloride (100 mL) was added dropwise over 40 min,followed by a methylene chloride rinse (25 mL). The mixture exothermedto 5° C. throughout the addition. After 30 min of stirring the reactionwas allowed to warm to room temperature. After 6 days of stirring atroom temperature. 1 N HCl (250 mL) was added dropwise with stirring atroom temperature. After stirring for 30 min, the organic phase wasisolated, dried (Na₂SO₄), and silica gel (100 g) was added to themixture with swirling. The mixture was suction filtered through a silicaplug (800 g) capped with celite and the fitration medium was rinsedthrough with the following rinses:

-   -   1. methylene chloride (4×200 mL): clear, colorless filtrate.    -   2. EtOAc (3×1000 mL): pale yellow filtrate.    -   3. EtOAc (1×1000 mL): clear, colorless filtrate.        The above filtration lots were concentrated under reduced        pressure.

Filtrate Lot Solvent Concentrate 1 CH₂Cl₂  0.2 grams 2 EtOAc 73.3 grams3 EtOAc 0.12 gramsLot 2 concentrate (73.3 g) was diluted with EtOAc (210 mL) and wasseeded with authentic 3-[(methylsulfonyl)amino]phenylboronic acid,pinacol ester. Heptane (630 mL) was then added dropwise to the productsolution at room temperature with stirring. Precipitation had occurred.The mixture was cooled to 1-2° C. for 1.5 h then suction filtered. Thecollected solids were rinsed with heptane (2×200 mL). The solids wereair-dried under suction for 20 min to afford 50.0 g (68.2%) of3-[(methylsulfonyl)amino]phenylboronic acid, pinacol ester as a whitesolid. ¹NMR (DMSO-d₆, δ 9.7 (s, 1H), 7.5-7.3 (m, 4H), 2.95 (s, 3H), 1.24(s, 12H); H₂O: 3.3(s).

Scheme II, step E: The final title compound (30 mg, 10%) was preparedfrom [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (260 mg,0.773 mmol, prepared in example 1),3-[(methylsulfonyl)amino]phenylboronic acid, pinacol ester (276 mg,0.929 mmol, prepared above), tetrakis(triphenylphosphine)palladium(0) (5mg, 0.004 mmol), 2 M sodium carbonate (280 mg in 1.3 mL water) and1,4-dioxane (5.2 mL) in a manner analogous to the procedure described inExample 2.

Electrospray-MS 425.1 (M*−1).

EXAMPLE 28

Preparation of Ethyl4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoate.

Preparation of 4-(ethoxycarbonyl)benzeneboronic acid.

4-Carboxybenzeneboronic acid (350 mg, 2.109 mmol) was dissolved inethanol (10 mL, absolute) in a 100 mL 3-neck round bottom flask, fittedwith a condenser, thermometer, stirbar and rubber plug. An ethanol/HClmixture (10 mL, pH approximately 3.0) was added, and the mixture washeated at reflux (70° C.) for one hour. The reaction mixture was thenallowed to cool to room temperature and stirred overnight. The reactionmixture was concentrated in a vacuum, then dissolved in ethyl acetate,and washed with water. The organic layer was dried with potassiumcarbonate, filtered, and concentrated under reduced pressure, yielding520 mg white solid. This material was purified via silica gelchromatography, utilizing a Chromatotron® with a 6000 μm rotor in a 1:1hexane:ethyl acetate solvent system, yielding 470 mg of a co-elutingmixture of unreacted starting material and product. This mixture waspurified by reverse phase chromatography on a Vydac C-18 column on agradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in wateryielding the intermediate title compound (350 mg, 85.5%) as a whitesolid.

-   Electrospray-MS 195.0 (M*+1).    Preparation of Final Title Compound.

Scheme II, step E: The title compound (6 mg, 1%, white foam) wasprepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine(505 mg, 1.502 mmol, prepared in example 1),4-(ethoxycarbonyl)benzeneboronic acid (350 mg, 1.804 mmol),dichlorobis(triphenylphosphine)palladium(II) (45 mg, 0.064 mmol), 2 Msodium carbonate (540 mg in 2.6 mL water), and 1,2-dimethoxyethane (10mL) in a manner analogous to the procedure described in Example 8. Thecrude material was purified utilizing a Chromatotron® with a 2000 μmrotor in a 1:1 hexane:ethyl acetate solvent system, yielding 20 mg of aco-eluting mixture of unreacted starting material and title compound.This mixture was further purified by reverse phase chromatography on aVydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroaceticacid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.

Electrospray-MS 406.0 (M*+1).

EXAMPLE 29

Preparation ofN-{4-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}acetamide.

Scheme III, step C: To a solution of{2-[4-(3-Aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (125mg, 0.3587 mmol, prepared in example 3) in methylene chloride (2.5 mL)in a 10 mL round-bottomed flask, in an ice bath, fitted with athermometer, and under a nitrogen system was added triethylamine (0.125mL, 0.8968 mmol). The mixture was cooled to 0° C. and acetyl chloride0.04 mL, 0.5381 mmol) was added by syringe. The mixture was allowed towarm to room temperature, and stirred overnight, under a nitrogensystem. The reaction was quenched with excess water, and the organiclayer was dried with anhydrous sodium sulfate, filtered, andconcentrated under reduced vacuum, yielding 265 mg viscous oil.Purification was conducted using a Chromatotron®, on a 4000 μm rotor andeluting with a 1:1 hexane:ethyl acetate solvent system, yielding thetitle compound (104 mg, 74%) as a slow crystallizing foam.

Electrospray-MS 391.0 (M*+1).

EXAMPLE 30

Preparation of2-Methyl-N-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}propanamide.

Scheme III, step C: To a solution of{2-[4-(3-aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (145mg, 0.416 mmol, prepared in example 3) dissolved in methylene chloride(2.8 mL, anhydrous), was added triethylamine (0.15 mL, 1.04 mmol) undera nitrogen system. The mixture was cooled to 0° C. and isobutyrylchloride (0.13 mL, 1.25 mmol) was added by syringe. The mixture wasallowed to warm to room temperature, and stirred overnight, under anitrogen system. The reaction was quenched with excess water, and theorganic layer was dried with anhydrous sodium sulfate, filtered, andconcentrated under reduced vacuum, yielding 280 mg viscous oil.Purification was conducted using a Chromatotron®, on a 4000 μm rotor andeluting with a 1:1 hexane:ethyl acetate solvent system, yielding thetitle compound (136 mg, 78%) as a slow crystallizing foam.

Electrospray-MS 419.0 (M*+1).

EXAMPLE 31

Preparation of[(Methylethyl)sulfonyl]{2-[4-(3-{[(methylethyl)sulfonyl]amino}phenyl)phenoxy]propyl}amine.

Scheme III, step B: To a solution of{2-[4-(3-aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (125mg, 0.3587 mmol, prepared in example 3) dissolved in methylene chloride(2.5 mL, anhydrous) was added triethylamine (0.125 mL, 0.8968 mmol)under a nitrogen system. The mixture was cooled to 0° C. and2-propanesulfonyl chloride (0.06 mL, 0.5381 mmol) was added by syringe.The mixture was allowed to warm to room temperature, and stirredovernight, under a nitrogen system. The reaction was quenched withexcess water, and the organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure, yielding 431mg viscous oil. Purification was conducted using a Chromatotron®, on a4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solventsystem, yielding 400 mg of two inseparable coeluting spots. This mixturewas purified by reverse phase chromatography on a Vydac C-18 column on agradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in waterover 45 minutes at 200 mL/min elution rate, yielding the title compound(16.7 mg, 1%) as a slow crystallizing foam.

Electrospray-MS 455.0 (M*+1).

EXAMPLE 32

Preparation of(2-{4-[4-(Aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride.

Scheme III, step A: In a 100 mL 3-neck flask, fitted with a thermometer,a stirbar and a condenser,{2-[4-(4-cyanophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (1.0 g,2.79 mmol, prepared in example 25), borane-methyl sulfide complex (13.95mL, 27.9 mmol), and tetrahydrofuran (33.5 mL) were combined and heatedat reflux, with stirring, at 70° C., overnight, under a nitrogen system.The reaction mixture was allowed to cool to room temperature, and 8.5 mLof 1:1 tetrahydrofuran:methyl alcohol mixture was added dropwise,slowly, until foaming ceased. Next, 5N sodium hydroxide was added, andthe reaction mixture was refluxed for 5 hours. The mixture was thenpermitted to cool to room temperature and extracted three times with 50mL of methylene chloride. The organic layer was dried with potassiumcarbonate, filtered, and concentrated under reduced vacuum, yielding2.47 g of viscous purple oil. This oil was dissolved into diethyl ether,and acidified with anhydrous hydrogen choride gas. The acid mixture wasallowed to stir at room temperature for 1 hour, forming a whiteprecipitate. The precipitate was captured by vacuum filtration yieldingthe title compound (1.34 g, 100%) as an off-white solid.

Electrospray-MS 363.0 (M*+1).

EXAMPLE 33

Preparation of[(Methylethyl)sulfonyl]({4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}methyl)amine.

Scheme III, step B: The final title compound (140 mg, 69.5%) wasprepared from(2-{4-[4-aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (150 mg, 0.430 mmol, prepared in example 32) methylenechloride (2.5 mL, anhydrous), triethylamine (0.07 mL, 0.471 mmol) and2-propanesulfonyl chloride (0.07 mL, 0.565 mmol) in a manner analogousto Example 29.Electrospray-MS 469.0 (M*+1).

EXAMPLE 34

Preparation of[(Methylethyl)sulfonyl](2-{4-[4-({[(trifluoromethyl)sulfonyl]amino}methyl)phenyl]phenoxy}propyl)amine.

Scheme III, step B: The final title compound (23 mg, 11%) was preparedfrom(2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (150 mg, 0.430 mmol, prepared in example 32) methylenechloride 2.5 mL, anhydrous) triethylamine (0.07 mL, 0.471 mmol) andtrifluoromethylsulfonyl chloride (9.06 mL, 0.565 mmol), in a manneranalogous to Example 29.

Electrospray-MS 495.0 (M*+1).

EXAMPLE 35

Preparation of2-Methyl-N-({4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}methyl)propanamide.

Scheme III, step C: The final title compound (59 mg, 19%) was preparedfrom(2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (250 mg, 0.717 mmol, prepared in example 32) methylenechloride (4.6 mL, absolute) triethylamine (0.07 mL, 0.8621 mmol), aindisobutyryl chloride (0.06 mL, 1.0345 mmol), in a manner analogous toExample 29.

Electrospray-MS 433.0 (M*+1).

EXAMPLE 36

Preparation of[(Methylethyl)sulfonyl]{2-[4-(4-{[(methylsulfonyl)amino]methyl}phenyl)phenoxy]propyl}amine.

Scheme III, step B: The final title compound (10 mg, 3%) was preparedfrom(2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[methylethyl)sulfonyl]aminehydrochloride (250 mg, 0.717 mmol, prepared in example 32) methylenechloride (4.6 mL, anhydrous) triethylamine (0.12 mL, 0.8621 mmol) andmethanesulfonyl chloride (0.08 mL, 1.0345 mmol), in a manner analogousto Example 29.

Electrospray-MS 441.0 (M*+1).

EXAMPLE 37

Preparation ofN-({4-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}methyl)acetamide.

Scheme III, step C: The final title compound (98 mg, 42%) was preparedfrom(2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (200 mg, 0.5739 mmol, prepared in example 32) methylenechloride (3.8 mL, anhydrous) triethylamine (0.12 mL, 0.6620 mmol) andacetyl chloride (0.08 mL, 0.6069 mmol), in a manner analogous to Example29.

Electrospray-MS 405.0 (M*+1).

EXAMPLE 38

Preparation of(tert-butoxy)-N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)carboxamide.

Preparation of 2,2,2-trifluoro-N-(2-phenylethyl)acetamide.

To a solution of phenethylamine (242 g, 2.0 moles) in dichloromethane(1.2 L) was added triethylamine (213 g, 2.1 moles) and was cooled to −5°C. Trifluoroacetic anhydride (441 g, 2.1 moles) was added to thereaction mixture dropwise over 10 min. During the addition the reactionmixture exothermed to 22° C. This mixture was stirred at roomtemperature for 30 min. Acetic acid (5 mL) was added and the mixture wasextracted with water (3×50 mL). The organic phase was co-evaporated withhexanes to afford 431 g (99.3%) of intermediate title compound,2,2,2-trifluoro-N-(2-phenylethyl)acetamide, as a solid mass that wascarried directly into the following reaction.Preparation of 2,2,2-trifluoro-N-[2-(4-iodophenyl)ethyl]acetamide.

To a room temperature solution of2,2,2-trifluoro-N-(2-phenylethyl)acetamide (431 g, 1.98 moles) inglacial acetic acid (1.5 L) was added water (400 mL), sulfuric acid (200g, 2.04 moles), periodic acid (105 g, 0.46 mol), and lastly iodine (201g, 0.791 mol). The mixture was first heated to 55° C., and then heatedto 70° C. over 2 h. This temperature course avoided excessive exothermduring the starting phase of the reaction. After 3 h, GC analysisindicated 10% starting material remained. Another portion of iodine (7g, 0.027 mol) and periodic acid (3.5 g, 0.015 mol) was introduced to thereaction mixture. Sublimed iodine that deposited on the upper region ofthe reactor was washed into the reaction with a minimum of acetic acid.The reaction mixture was further heated at 70° C. for 30 min and wasallowed to stand at room temperature overnight.

Sodium acetate (351 g, 4.08 moles) was added to neutralize the sulfuricacid, followed by the addition of sodium sulfite until the mixturedecolorized. The mixture was cooled to 10° C. and was filtered. Thefilter cake was washed with 1:1 acetic acid-water (400 mL), water (500mL) and was reslurried in 1:9 acetic acid-water (1 L). After a finalwater wash and reslurry with water (1 L), the collected solids werefiltered and vacuum dried at 45° C. This procedure afforded 354 g(52.1%) of intermediate title compound,2,2,2-trifluoro-N-[2-(4-iodophenyl)ethyl]acetamide, as a white powder.

¹H NMR (CDCl₃, 300 MHz): δ 7.66 (d, 2H, J=8.4); 6.94 (d, 2H, J=8.4);6.31 (br s, 1 H); 3.59 (q, 2H, J=6.9); 2.84 (t, 2H, J=6.9).

Preparation of pinacolborane.

A 5 L round bottom flask was charged with pinacol (177 g, 1.5 moles) andCH₂Cl₂ (1.6 L). The borane-dimethylsulfide (10 M,159 mL, 0.16 mol) wasadded to the flask via cannula and the mixture was stirred at 0° C. for4 h. The reaction mixture was then allowed to warm to room temperatureovernight with stirring.

After 17 h, the reaction mixture was still evolving some gas (hydrogen);

however, the reaction was warmed and subjected slowly to reducedpressure (760 mm to 200 mm). This procedure allowed the distillation ofCH₂Cl₂ (1.3 L) from the reaction. The remaining liquid was transferredby cannula to a 500 mL flask and was subjected to a slow pressurereduction from atmospheric to 50 mm over 2.5 h. Some initial foaming wasobserved in the viscous liquid due to continued off-gassing thatsubsided in time. This process afforded 157 g (81.7%) of crudepinacolborane that was suitable for the subsequent reactions.Preparation of 2,2,2-trifluoro-N-[2-(4-boronicacid)phenyl)ethyl]acetamide, pinacol ester.

In a manner analogous to the procedure described by Murata, M., et al.,J. Org. Chem, 62, 6458-64592 (1997),2,2-trifluoro-N-[2-(4-iodophenyl)ethyl]acetamide (313 g, 0.912 mol),Et₃N (277 g, 2.73 moles), acetonitrile (2.5L) and Pd(dppf)₂Cl₂ catalystwere combined in a 5 L reactor and the resulting solution was evacuatedand purged with nitrogen three times. The pinacolborane (146 g, 1.14moles) generated above was added and the mixture was heated to 70° C.for 3.5 h. GC analysis of an aliquot indicated extensive consumption ofstarting 2,2,2-trifluoro-N-[2-(4-iodophenyl)ethyl]acetamide (0.4%) alongwith the generation of intermediate title compound (76.9%). The mixturewas cooled to room temperature, concentrated to an oil and redissolvedin heptane. The heptane was decanted away from an insoluble blackresidue and concentrated to 210 g of a yellow oil. The heptane insolubletar was diluted with heptane (500 mL) and water (500 mL). This mixturewas warmed to 70° C. and separated. The heptane phase was concentratedto an oil. The heptane-extracted products were combined and purified viaBiotage chromatography (2.5 Kg silica gel, presaturated with CH₂Cl₂).Fractions containing 96-98.5% intermediate title compound (by GC) werecombined and concentrated to a solid that was triturated withcyclohexane (100 mL), filtered and dried under reduced pressure toafford 120 g of intermediate title compound. Mixed fractions containingintermediate title compound and 20-52%2,2,2-trifluoro-N-(2-phenylethyl)acetamide (byproduct obtained byreductive removal of the iodine atom) were combined, concentrated,crystallized with cyclohexane. This crop was triturated with cyclohexaneto afford additional intermediate title compound (9 g). This treatmentresulted in the total isolation of 129 g (31.9%) of desired intermediatetitle compound, 2,2,2-trifluoro-N-[2-(4-(boronicacid)phenyl)ethyl]acetamide, pinacol ester, as a white solid: ¹H NMR(CDCl₃, 300 MHz): δ 7.78 (d, 2H, J=7.8); 7.20 (d, 2H, J=7.5); 6.21 (brs, 1H); 3.62 (q, 2H, J=6.6); 2.90 (t, 2H, J=6.6); 1.32 (s, 12H).Preparation of tert-butyl {2,2,2-trifluoro-N-[2-(4-(boronicacid)phenyl)ethyl]acetylamino}formate, pinacol ester.

To a solution of2,2,2-trifluoro-N-[2-(4-boronicacid)phenyl)ethyl]acetamide, pinacolester (100 g, 0.291 mol) in CH₂Cl₂ (1.0 L) was added 4-N,Ndimethylaminopyridine (1.78 g, 0.0146 mol), followed by di-tert-butyldicarbonate (70.0 g, 0.320 mol). The resulting mixture was allowed tostir at room temperature overnight. After 17 h, the reaction mixture waswashed with deionized water (2×300 mL). The organic phase wasconcentrated to a solid that was dried under vacuum to afford 128.9 g(99.8%) intermediate title compounde as a white powder.

(CDCl₃, 300 MHz): δ 7.75 (d, 2H, J=4.8); 7.22 (d, 2H, J=4.5); 3.92 (t,2H, J=4.8); 2.91 (t, 2H, J=4.5); 1.48 (s, 9H); 1.33 (s, 12H).

Preparation of 4-{2-[(tert-butoxy)carbonylamino]ethyl}boronic acid,pinacol ester.

To a stirred solution of of tert-butyl {2,2,2-trifluoro-N-[2-(4-(boronicacid)phenyl)ethyl]acetylamino}formate, pinacol ester (125 g, 0.282 mol)in n-propanol (750 mL) and diethyl ether (150 mL) was added a solutionof sodium carbonate (44.8 g, 0.423 mol) in water (500 mL). After 2 h,HPLC analysis indicated nearly complete hydrolysis of thetrifluoroacetamide group. The aqueous phase was separated and theorganic phase was concentrated to a thick white paste. This paste wassuspended in pentane and filtered. The filtrate was similarlyconcentrated, resuspended in pentane/diethyl ether (1:1) and filtered toafford white solids. The crops were combined and dried under reducedpressure to give 106 g (108%) of intermediate title compound,4-{2-[(tert-butoxy)carbonylamino]ethyl}boronic acid, pinacol ester as awhite powder. (CDCl₃, 300 MHz): δ 7.67 (d, 2H, J=4.8); 7.24 (d, 2H,J=4.5); 6.01 (br s, 1H); 3.30 (q, 2H, J=4.2); 2.81 (t, 2H, J=4.2); 1.39(s, 9H); 1.32 (s, 12H).

Preparation of Final Title Compound.

Scheme II, step E:[2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (1.875 g, 5.576mmol, prepared in example 1),4-{2-[(tert-butoxy)carbonylamino]ethyl}boronic acid, pinacol ester,(2.26 g, 6.508 mmol), dichlorobis(triphenylphosphine)palladium(II) (155mg, 0.221 mmol), 2M sodium carbonate (1.96 g in 9.25 mL water) and1,2-dimethoxyethane (36 mL) were combined in a 100 mL 3-neck roundbottom flask, fitted with a condenser, stirbar, and thermometer, andheat at reflux in a nitrogen system to 85° C. overnight. The roomtemperature reaction mixture was quenched with water and extracted threetimes with 25 mL of methylene chloride. The organic extracts werecombined, dried over anyhydrous magnesium sulfate, filtered throughcelite, and concentrated under reduced pressure, yielding 4.0 g brownviscous oil. This material was purified via silica gel chromatography,utilizing a Hewlett-Packard HPLC 2000 with 2 silica cartridges in a 1:1hexane:ethyl acetate solvent system, yielding the final title compound(610 mg, 29%),(tert-butoxy)-N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)carboxamide,as a white solid.

Electrospray-MS 477.0 (M*+1).

EXAMPLE 39

Preparation of(2-{4-[4-(2-Aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride.

(tert-Butoxy)-N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)carboxamide(410 mg, 0.860 mmol, prepared in example 38), trifluoroacetic acid (0.86mL), and methylene chloride (5.75 mL) were combined and stirred, bystirbar, in a 15 mL round bottom flask, in a nitrogen system, at roomtemperature, for one hour. The reaction mixture was then concentratedunder reduced pressure, and dissolved in excess 5N sodium hydroxide, andextracted three times with 25 mL of methylene chloride. Next the organicextracts were combined, washed with 50 mL of water, dried with potassiumcarbonate, filtered, and concentrated under reduced vacuum, yielding 480mg of crude material. This crude material was dissolved in diethylether, and anhydrous hydrogen chloride gas was bubbled through thesolution, until it was acidic. Next, the acidic solution was allowed tostir, by stirbar, for an additional hour, and then was vacuum filtered,capturing the white precipitate and drying it in a vacuum oven at 40° C.for 30 minutes, yielding the title compound (305 mg, 94%) as a yellowsolid.

Electrospray-MS 377.0 (M*+1).

EXAMPLE 40

Preparation of[(Methylethyl)sulfonyl](2-{4-[4-(2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenoxy}propyl)amine.

Scheme II, step B: To a 10 mL round-bottomed flask, in an ice bath,fitted with a thermometer, and under a nitrogen atmosphere, of(2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (150 mg, 0.3984 mmol, prepared in example 39) dissolved inmethylene chloride (2.7 mL) was added triethylamine (0.07 mL, 0.478mmol). Once the mixture was cooled to 0° C., 2-propanesulfonyl chloride(0.05 mL, 0.4382 mmol) was added by syringe, and the mixture wasgradually warmed to room temperature, with stirring overnight. Thereaction was quenched with excess water, and the organic layer was driedwith anhydrous sodium sulfate, filtered, and concentrated under vacuum,yielding 265 mg viscous oil. Purification was conducted using aChromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethylacetate solvent system, yielding the title compound (200 mg, 100%) as aslow crystallizing foam.

Electrospray-MS 483.0 (M*+1).

EXAMPLE 41

Preparation ofN-(2-{4-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)acetamide.

Scheme III, step C: The title compound (108 mg, 39%, slow crystallizingfoam) was prepared from(2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylenechloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), andacetyl chloride (0.05 mL, 0.664 mmol) in a manner analogous to theprocedure described in Example 40.

Electrospray-MS 419.0 (M*+1).

EXAMPLE 42

Prepation of2-Methyl-N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)propanamide.

Scheme III, step C: The title compound (110 mg, 37%, slowcrystallizing-foam) was prepared from(2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylenechloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), andisobutyryl chloride (0.07 mL, 0.664 mmol) in a manner analogous to theprocedure described in Example 40.

Electrospray-MS 447.0 (M*+1).

EXAMPLE 43

Preparation of[(Methylethyl)sulfonyl]{2-[4-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)phenoxy]propyl}amine.

Scheme III, step B: The title compound (318 mg, 100%, slowcrystallizing-foam) was prepared from(2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylenechloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), andmethanesulfonyl chloride (0.05 mL, 0.664 mmol) in a manner analogous tothe procedure described in Example 40.

Electrospray-MS 455.0 (M*+1).

EXAMPLE 44

Preparation of[(Methylethyl)sulfonyl](2-{4-[4-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)phenyl]phenoxy}propyl)amine.

Scheme III, step B: The title compound (130 mg, 38%, slowcrystallizing-foam) was prepared from(2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylenechloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), andtrifluoromethanesulfonyl chloride (0.07 mL, 0.664 mmol) in a manneranalogous to the procedure described in Example 40.

EXAMPLE 45

Preparation of[(methylethyl)sulfonyl](2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenoxy}propyl)amine.

[2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.595mmol), cyclopentylboronic acid (60 mg, 0.714 mmol),([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (4 mg, 0.024 mmol), and 2M sodium hydroxide (1 mL) werecombined with THF (4 mL) in a 15 ml round-bottomed flask, fitted with acondenser, and stirbar, in a temperature regulated oil bath, andrefluxed at 65° C. overnight in a nitrogen system. After cooling to roomtemperature, the reaction mixture was quenched with 15 mL of water, andextracted three times with 15 mL ethyl acetate. The organic extractionswere combined and dried with magnesium sulfate, then filtered throughCelite®, and concentrated in-vacuo, yielding 210 mg viscous black oil.This material was further purified using a 4000 uM rotor on aChromatotron in a 1:1 hexanes:ethyl acetate solvent system to providethe title compound (50 mg, 16%) as white crystals.

Electrospray-MS (511.4; singlet) M*−1

Elemental Analysis:

-   C(Theory): 56.23 C(Found): 55.92-   H(Theory): 7.08 H(Found): 6.98-   N(Theory): 5.46 N(Found): 5.60

EXAMPLE 46

Preparation ofN-acetyl-N-{3-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}acetamide.

{2-[4-(3-Aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (150mg, 0.3764 mmol, see example 3), triethylamine 0.125 mL, 0.8968 mmol),and methylene chloride 2.5 mL) were combined in a 15 mL round-bottomed,flask, fitted with stirbar, and cooled to 0° C. in an ice bath, in anitrogen system. Acetyl chloride (0.04 mL, 0.5381 mmol) was added bysyringe maintaining a temperature of 0-5° C. The reaction was allowed tostir overnight, gradually becoming room temperature. The reactionmixture was quenched with 15 mL of water, and extracted three times with15 mL methylene chloride. The organic extractions were combined, anddried with magnesium sulfate, filtered, and concentrated in-vacuo,yielding 265 mg brown foam. This material was further purified by usinga 4000 uM rotor on a Chromatotron, in a 1:1 hexanes:ethyl acetatesolvent system to provide the title compound (74 mg, 48%) as whitecrystals.

Electrospray-MS (434.0; singlet) M*+1

EXAMPLE 47

Preparation of Methyl4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoate.

[2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (500 mg, 1.487mmol) was combined with bis(pinicolato)diboron (415 mg, 1.636 mmol),potassium acetate (440 mg, 4.461 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex(0.045 mmol) and dimethylformamide (10 mL) in a 3-neck round bottomedflask fitted with a thermometer, stirbar, condenser, and in a nitrogensystem. This reaction mixture was refluxed to 80° C. with stirring, forthree hours. The reaction mixture was cooled to room temperature, and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex(0.045 mmol) was added, followed by 2M sodium carbonate (3.7 mL), andrefluxed to 80° C., with stirring, overnight. The reaction was cooled toroom temperature, and diluted with 100 mL of diethyl ether, and washedwith 100 mL water and 100 mL brine. Organic layer was dried withpotassium carbonate, filtered and concentrated in-vacuo, yielding 1.53 gof brown solid. This material was further purified using a 6000 uM rotoron a Chromatotron in a 1:1 hexanes:ethyl acetate solvent system toprovide the title compound (50 mg, 9%) as yellow crystals.

Electrospray-MS (393.0; singlet) M*+1

Elemental Analysis:

-   C(Theory): 61.36 C(Found): 60.32-   H(Theory): 6.44 H(Found): 6.27-   N(Theory): 3.56 N(Found): 3.56

EXAMPLE 48

Preparation of4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoicacid.

Methyl4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoate(30 mg, 0.077 mmol), lithium hydroxide (11 mg, 0.268 mmol), THF (1.2mL), methanol (0.4 mL) and deionized water (0.4 mL) were combined in a15 mL round bottomed flask and stirred at room temperature overnight.The reaction mixture was concentrated in-vacuo, and dissolved in 1 Nsodium hydroxide. This solution was acidified (pH=2) with 1 Nhydrochloric acid, and was extracted three times with methylenechloride. The organic extractions were combined, washed with 15 mLwater, dried with magnesium sulfate, filtered, and concentratedin-vacuo, yielding 85 mg of yellow solid. This material was furtherpurified using a 1000 uM rotor on a Chromatotron in a 1:1 methylenechloride:ethyl acetate solvent system to provide the title compound (65mg, 100%) as waxy brown paste.

Electrospray-MS (393.0; singlet) M*+1

EXAMPLE 49

Preparation of[(2S)-2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine.

Preparation of (2S)-2-(4-bromophenoxy)propylamine hydrochloride.

Scheme II, step C: (2S)-2-(4-bromophenoxy)propanamide (4.0 g, 16.39mmol, see example 1A), borane dimethyl sulfide complex (16.4 mL, 163.9mmol)), and tetrahydrofuran (50 mL) were combined in a 2000 mL 3-neckround bottomed flask, fitted with a thermometer, reflux condenser, andaddition funnel. Under a nitrogen system the reaction mixture wasrefluxed at 70° C. overnight with stirring. The reaction mixture wascooled, and 1:1 tetrahydrofuran:methanol (50 mL) was added slowly. Oncefoaming had ceased, 5 N sodium hydroxide (150 mL) was added, and thereaction mixture was refluxed at 55° C., with stirring, for 5 hours.Next the reaction mixture was cooled to room temperature, and extractedthree times with 400 mL methylene chloride. The organic extractions werecombined and dried with sodium sulfate, filtered and concentratedin-vacuo, yielding 3.73 g yellow oil.

This material was dissolved in excess diethyl ether, and anhydroushydrogen chloride gas was bubbled through the solution with stirring,until white crystals had precipitated out (pH=2). The solution wasstirred for an additional hour, before the precipitate was vacuumfiltered off, and washed two times with 100 mL of diethyl ether. Thisprecipitate was dried in a vacuum oven for 2 hours at 40° C. yieldingthe intermediate title compound, (2S)2-(4-bromophenoxy)propylamine HCl,(1.48 g) as a white powder.

Preparation of Final Title Compound.

Scheme II, step D: The above prepared (2S)-2-(4-bromophenoxy)propylaminewas combined in a 500 mL 3-neck round bottomed flask with triethylamine(5.7 mL) and methylene chloride (110 mL), fitted with a thermometer,stirbar, and in a nitrogen system. The reaction mixture was cooled to 0°C. in an ice bath, with stirring, and isopropylsulfonyl chloride (2.75mL, 24.585 mmol) was added by syringe. The mixture was stirredovernight, gradually becoming room temperature. The reaction wasquenched with 100 mL water, and extracted two times with 100 mLmethylene chloride. The organic extractions were combined, and washedwith 200 mL brine, dried with sodium sulfate, filtered and concentratedin-vacuo, yielding 2.08 g viscous brown oil. This material was furtherpurified using one Waters Prep-Pak® on a Waters Prep 2000 HPLC, in a 3:1hexanes:ethyl acetate solvent system to provide the final title compound(1.63 g, 30%) as a viscous yellow oil.

Electrospray-MS (336.0, 338.0; doublet) M*+1

Elemental Analysis:

-   C(Theory): 42.87 C(Found): 42.34-   H(Theory): 5.40 H(Found): 5.05-   N(Theory): 4.17 N(Found): 4.33

EXAMPLE 50

Preparation of[(2S)-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenoxy)propyl][(methylethyl)sulfonyl]amine.

Scheme II, step E:[(2S)-2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (1.61 g,4.788 mmol, see example 1A), 3-[(methylsulfonyl)amino]phenylboronicacid, pinacol ester (1.80 g, 6.033 mmol, example 27),tetrakis(triphenylphosphine)palladium(0) (360 mg, 0.3112 mmol), 2Msodium carbonate (8.15 mL) and dimethylene glycol (32 mL) were combinedinto a 100 mL round-bottomed flask, fitted with a condenser, andstirbar, in a temperature regulated oil bath, and refluxed at 85° C.overnight in a nitrogen system. After cooling to room temperature, thereaction mixture was quenched with 50 mL of water, and extracted threetimes with 50 mL ethyl acetate. The organic extractions were combinedand dried with magnesium sulfate, then filtered through Celite®, andconcentrated in-vacuo, yielding 2.76 g viscous black oil. This materialwas further purified using one Waters Prep-Pak® on a Waters Prep 2000HPLC, in a 3:1 hexanes:ethyl acetate solvent system to provide the titlecompound (640 mg, 31%) as viscous yellow oil.

Electrospray-MS (427.0; singlet) M*−1

Elemental Analysis:

-   C(Theory): 53.50 C(Found): 52.91-   H(Theory): 6.14 H(Found): 6.08-   N(Theory): 6.57 N(Found): 6.47

EXAMPLE 51

Preparation of[(2R)-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenoxy)propyl][(methylethyl)sulfonyl]amine.

Scheme II, step E:[(2R)-2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (1.01 g,3.004 mmol, see example 1B), 3-[(methylsulfonyl)amino]phenylboronicacid, pinacol ester (1.125 g, 3.785 mmol, example 27),tetrakis(triphenylphosphine)palladium(0) (226 mg, 0.1953 mmol), 2Msodium carbonate (5.1 mL) and dimethylene glycol (20 mL) were combinedinto a 100 mL round-bottomed flask, fitted with a condenser, andstirbar, in a temperature regulated oil bath, and refluxed at 85° C.overnight in a nitrogen system. After cooling to room temperature, thereaction mixture was quenched with 50 mL of water, and extracted threetimes with 50 mL ethyl acetate. The organic extractions were combinedand dried with magnesium sulfate, then filtered through Celite®, andconcentrated in-vacuo, yielding 1.07 g viscous black oil. This materialwas further purified using one Waters Prep-Pak® on a Waters Prep 2000HPLC, in a 3:1 hexanes:ethyl acetate solvent system to provide the titlecompound (340 mg (0.80, 27%) as viscous yellow oil.

Electrospray-MS (427.0; singlet) M*−1

Elemental Analysis:

-   C(Theory): 53.50 C(Found): 53.31-   H(Theory): 6.14 H(Found): 6.14-   N(Theory): 6.57 N(Found): 6.41

EXAMPLE 52

Preparation of4-[4-((1S)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile.

Scheme II, step E:[(2S)-2-(4-Bromophenoxy)propyl][(methylethyl)sulfonyl]amine (325 mg,0.9665 mmol, see example 1A), 4-cyanoboronic acid (179 mg, 1.218 mmol),tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.063 mmol), 2M sodiumcarbonate (1.65 mL) and dimethylene glycol (6.45 mL) were combined intoa 50 mL round-bottomed flask, fitted with a condenser, and stirbar, in atemperature regulated oil bath, and refluxed at 85° C. overnight in anitrogen system. After cooling to room temperature, the reaction mixturewas quenched with 25 mL of water, and extracted three times with 25 mLethyl acetate. The organic extractions were combined and dried withmagnesium sulfate, then filtered through Celite®, and concentratedin-vacuo, yielding 590 mg viscous black oil. This material was furtherpurified using a 4000 uM rotor on a Chromatotron in 1:1 hexanes:ethylacetate solvent system to provide the title compound (130.5 mg, 38%) asviscous yellow oil.

Electrospray-MS (359.0; singlet) M*−1

Elemental Analysis:

-   C(Theory): 63.66 C(Found): 63.11-   H(Theory): 6.19 H(Found): 6.02-   N(Theory): 7.81 N(Found): 7.78

The ability of compounds of formula I to potentiate glutamatereceptor-mediated response may be determined using fluorescent calciumindicator dyes (Molecular Probes, Eugene, Oreg., Fluo-3) and bymeasuring glutamate-evoked efflux of calcium into GluR4 transfectedHEK293 cells, as described in more detail below.

In one test, 96 well plates containing confluent monolayers of HEK 293cells stably expressing human GluR4B (obtained as described in EuropeanPatent Application Publication Number EP-A1-583917) are prepared. Thetissue culture medium in the wells is then discarded, and the wells areeach washed once with 200 μl of buffer (glucose, 10 mM, sodium chloride,138 mM, magnesium chloride, 1 mM, potassium chloride, 5 mM, calciumchloride, 5 mM, N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid],10 mM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutesin the dark with 20 μM Fluo3-AM dye (obtained from Molecular ProbesInc., Eugene, Oreg.) in buffer in each well. After the incubation, eachwell is washed once with 100 μl buffer, 200 μl of buffer is added andthe plates are incubated for 30 minutes.

Solutions for use in the test are also prepared as follows. 30 μM, 10μM, 3 μM and 1 μM dilutions of test compound are prepared using bufferfrom a 10 mM solution of test compound in DMSO. 100 μM cyclothiazidesolution is prepared is by adding 3 μl of 100 mM cyclothiazide to 3 mLof buffer. Control buffer solution is prepared by adding 1.5 μl DMSO to498.5 μl of buffer.

Each test is then performed as follows. 200 μl of control buffer in eachwell is discarded and replaced with 45 μl of control buffer solution. Abaseline fluorescent measurement is taken using a FLUOROSKAN IIfluorimeter (Obtained from Labsystems, Needham Heights, Mass., USA, aDivision of Life Sciences International Plc). The buffer is then removedand replaced with 45 μl of buffer and 45 μl of test compound in bufferin appropriate wells. A second fluorescent reading is taken after 5minutes incubation. 15 μl of 400 μM glutamate solution is then added toeach well (final glutamate concentration 100 μM), and a third reading istaken. The activities of test compounds and cyclothiazide solutions aredetermined by subtracting the second from the third reading(fluorescence due to addition of glutamate in the presence or absence oftest compound or cyclothiazide) and are expressed relative to enhancefluorescence produced by 100 μM cyclothiazide.

In another test, HEK293 cells stably expressing human GluR4 (obtained asdescribed in European Patent Application Publication No. EP-A1-0583917)are used in the electrophysiological characterization of AMPA receptorpotentiators. The extracellular recording solution contains (in mM): 140NaCl, 5 KCl, 10 HEPES, 1 MgCl₂, 2 CaCl₂, 10 glucose, pH=7.4 with NaOH,295 mOsm kg-1. The intracellular recording solution contains (in mM):140 CsCl, 1 MgCl₂, 10 HEPES,(N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA(ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH=7.2 with CsOH,295 mOsm kg-1. With these solutions, recording pipettes have aresistance of 2-3 MΩ. Using the whole-cell voltage clamp technique(Hamill et al.(1981)Pflügers Arch., 391: 85-100), cells arevoltage-clamped at −60 mV and control current responses to 1 mMglutamate are evoked. Responses to 1 mM glutamate are then determined inthe presence of test compound. Compounds are deemed active in this testif, at a test concentration of 10 μM or less, they produce a greaterthan 10% increase in the value of the current evoked by 1 mM glutamate.

In order to determine the potency of test compounds, the concentrationof the test compound, both in the bathing solution and co-applied withglutamate, is increased in half log units until the maximum effect wasseen. Data collected in this manner are fit to the Hill equation,yielding an EC₅₀ value, indicative of the potency of the test compound.Reversibility of test compound activity is determined by assessingcontrol glutamate 1 mM responses. Once the control responses to theglutamate challenge are re-established, the potentiation of theseresponses by 100 μM cyclothiazide is determined by its inclusion in boththe bathing solution and the glutamate-containing solution. In thismanner, the efficacy of the test compound relative to that ofcyclothiazide can be determined.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of formula I or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable diluent or carrier.

The pharmaceutical compositions are prepared by known procedures usingwell-known and readily available ingredients. In making the compositionsof the present invention, the active ingredient will usually be mixedwith a carrier, or diluted by a carrier, or enclosed within a carrier,and may be in the form of a capsule, sachet, paper, or other container.When the carrier serves as a diluent, it may be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. The compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols, ointments containing, forexample, up to 10% by weight of active compound, soft and hard gelatincapsules, suppositories, sterile injectable solutions, and sterilepackaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia,calcium phosphate, alginates, tragcanth, gelatin, calcium silicate,micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 mg to about 500 mg, more preferably about5 mg to about 300 mg (for example 25 mg) of the active ingredient. Theterm “unit dosage form” refers to a physically discrete unit suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient. The following formulationexamples are illustrative only and are not intended to limit the scopeof the invention in any way.

Formulation 1 Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Active Ingredient 250 Starch, dried200 Magnesium Stearate  10 Total 460

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2 Tablets each containing 60 mg of active ingredient aremade as follows: Quantity (mg/tablet) Active Ingredient 60 Starch 45Microcrystalline Cellulose 35 Polyvinylpyrrolidone 4 SodiumCarboxymethyl Starch 4.5 Magnesium Stearate 0.5 Talc 1 Total 150

As used herein the term “active ingredient” refers to a compound offormula I. The active ingredient, starch, and cellulose are passedthrough a No. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

As used herein the term “patient” refers to a mammal, such as a mouse,guinea pig, rat, dog or human. It is understood that the preferredpatient is a human.

As used herein, the terms “treating” or “to treat” each mean toalleviate symptoms, eliminate the causation either on a temporary orpermanent basis, or to prevent or slow the appearance of symptoms of thenamed disorder. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

As used herein, the term “effective amount” refers to the amount of acompound of formula I which is effective, upon single or multiple doseadministration to a patient, in treating the patient suffering from thenamed disorder.

An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of mammal; its size, age, and general health; thespecific disease or disorder involved; the degree of or involvement orthe severity of the disease or disorder; the response of the individualpatient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The compounds of formula I can be administered by a variety of routesincluding oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, bucal or intranasal routes. Alternatively, the compoundsof formula I may be administered by continuous infusion. A typical dailydose will contain from about 0.01 mg/kg to about 100 mg/kg of thecompound of formula I. Preferably, daily doses will be about 0.05 mg/kgto about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25mg/kg.

1. A compound of the formula:

wherein R¹ represents an unsubstituted or substituted aromatic group, oran unsubstituted or substituted heteroaromatic group; R² representsisopropyl; R⁵ represents hydrogen; and R⁶ represents (1-6C)alkyl; or apharmaceautically acceptable salt thereof but excluding the compound[(methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxy]propyl}amine.2. A compound according to claim 1 wherein R⁶ represents methyl.
 3. Acompound according to claim 2 wherein R¹ represents an unsubstituted orsubstituted aromatic group.
 4. A compound according to claim 2 whereinR¹ represents a naphthyl group or a phenyl, furyl, thienyl or pyridylgroup which is unsubstituted or substituted by one or two substitutesselected independently from halogen; nitro; cyano; hydroxymino;(1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C) cycloalkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO orOCONR¹³, R⁹ represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl,(3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or(3-8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently representshydrogen or (1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together withthe nitrogen atom to which they are attached form an azetidnyl,pyrrodinyl, piperdinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropryanyl;dihydrothiazolyl; (1-4C)alkoxycarbonyldiydrothlazolyl;(1-4)alkoxycarbonyldimethyldihydro-thiazolyl; tetrahydro-thienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴-(L^(a))_(n)-X²-(L^(b))_(m) in which X² represents a bond O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH orCH═CH, L^(a) and L^(b) each represents(1-4C)alkalyne, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen,nitro, cyano, hydroxyimino, (1-10C)alkyl, (2-10C)alkenyl,(2-10C)alkynyl, (3-8C)-cycloalkyl,4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl,cyano(2-10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ in which x is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NH¹⁷, NHCONH, OCONR¹⁹,N(CO(1-4C)alkyl)CO, or NR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl,phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,(1-4C)alkylaminosulfonyl(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino-(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cyctoalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azelidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 5. Acompound according to claim 3 wherein R¹ represents an unsubstituted orsubstituted phenyl.
 6. A compound according to claim 5 wherein thephenyl is substituted by halogen; nitro; cyano; (1-10C)alkyl;(2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR₁₂CO, NR₁₂COCOO orOCONR¹³, R⁹ represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl,(3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or(3-8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently representshydrogen or (1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together withthe nitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazlnyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl;(1-4C)alkoxycarbonyldimethyldihydro-thiazolyl; tetrahydro-thienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothlenyl; benzimidazolyl; and a group of formulaR¹⁴-(L^(a))_(n)-X²-(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen,nitro, cyano, hydroxylmino, (1-10C) alkyl, (2-10C)alkenyl,(2-10C)alkynyl, (3-8C)-cycloalkyl,4-(1,1-dioxotetrahydro-1,2-thiaezinyl), halo(1-10C)alkyl,cyano(2-10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ in which z is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹,N(CO(1-4C)alkyl)CO, or NR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl,phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,(1-4C)alkylaminosutfonyl(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)atkylsulfonylamino-(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or anaromatic or heleroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 7. Acompound according to claim 6 wherein the phenyl is substituted by agroup of formula R¹⁴-(L^(a))_(n)-X²-(L^(b))_(m) wherein n and m are both0, and X² is a bond.
 8. A compound according to claim 7 wherein R¹⁴represents a phenyl which is unsubstituted or substituted by one or twoof halogen, nitro, cyano, hydroxyimino, (1-10C)alkyl, (2-10C)alkenyl,(2-10C)alkynyl, (3-8C)-cycloalkyl,4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl,cyano(2-10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ in which z is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹,N(CO(1-4C)alkyl)CO, or NR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl,phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,(1-4C)alkylaminosulfonyl(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino-(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 9. Acompound according to claim 8 wherein R¹⁴ represents a phenyl which issubstituted by one or two of halogen, nitro, cyano, (1-10C) alkyl,(2-10C)alkenyl, halo(1-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and(CH₂)_(z)X³R¹⁵ in which z is 0 or an integer of from 1 to 4, X³represents O, S, NR¹⁶, CO, CH(OH), COO, OCO, CNR¹⁷, NR¹⁸CO, NHSO₂,SO₂NH, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹, N(CO(1-4C)alkyl)CO, or NR¹⁹COO, R¹⁵represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl,(1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl,(1-4C)alkylaminosulfonyl(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino-(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl; (3-8C)-cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁶ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
 10. Acompound according claim 9 wherein R¹⁴ represents a phenyl which issubstituted by one or two of halogen, nitro, cyano, (1-10C) alkyl,halo(1-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶,COO, CONR¹⁷, NR¹⁸CO, NHSO₂, SO₂NH, OCONR¹⁹, N(CO(1-4C)alkyl)CO, orNR¹⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (3-10C)alkenyl, (3-8C)-cycloalkyl,(1-4C)alkylaminosulfonyl(1-4C)alkyl, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform a pyrrolidinyl, piperdinyl or morpholino group.
 11. A compoundselected from the group consisting of:[2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine;[(methylethyl)sulfonyl]{2-[4-(4-(3-thienyl)phenyl)phenoxy]propyl}amine;{2-[4-(3-aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;[(methylethyl)sulfonyl][2-(4-phenylphenoxy)propyl]amine;2-[4-(2-chlorophenyl)phenoxy]propyl)[(methylethyl)sulfonyl]amine;[(methylethyl)sulfonyl]{2-[4-(3-methylphenyl)phenoxy]propyl)}amine;{2-[4-(4-chlorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;{2-[4-(3-chlorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;[(methylethyl yl)phenoxy)propyl][(methylethyl)sulfonyl]amine;[(methylethyl)sulfonyl]{2-[4-(4-methylphenyl)phenoxy]propyl}amine;3-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzaldehyde;[(methylethyl)sulfonyl](2-{4-[3-(trifluoromethyl)phenyl]phenoxy}propyl)amine;2-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzaldehyde;[(methylethyl)sulfonyl](2-{4-[4-(trifluoromethyl)phenyl]phenoxy}propyl)amine:{2-[4-(4-methoxyphenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;{2-[4-(2-fluorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;{2-[4-(4-fluorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;{2-[4-(3-methoxyphenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;{2-[4-(3-fluorophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;)sulfonyl]{2-[4-(2-methylphenyl)phenoxyl]propyl}amine;[(methylethyl)sulfonyl]{2-[4-(4-(2-thienyl)phenyl)phenoxy]propyl}amine;4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzaldehyde;[2-4-(2H-benzo[3,4-d]1,3-dioxolan-5-[(methylethyl)sulfonyl](2-{4-[2-(trifluoromethyl)phenyl]phenoxy}propyl)amine;{2-[4-(4-cyanophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine;2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethanenitrile;[(methylethyl)sulfonyl][2-(4-{3-[(methylsulfonyl)amino]phenyl}phenoxy)propyl]amine;ethyl4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoate;N-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}acetamide;2-methyl-N-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}propanamide;[(methylethyl)sulfonyl]{2-[4-(3-{[(methylethyl)sulfonyl]amino}phenyl)phenoxy]propyl}amine;(2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride;[(methylethyl)sulfonyl]({4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}methyl)amine;{(methylethyl)sulfonyl](2-{4-[4-({[(trifluoromethyl)sulfonyl]amino}methyl)phenyl]phenoxy}propylamine;2-methyl-N-({4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}methyl)propanamide;{[(methylethyl)sulfonyl]{2-[4-(4-{[(methylsulfonyl)amino]methyl}phenyl)phenoxy]propyl}amine;N-({4-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}methyl)acetamide;(tert-butoxy)-N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)carboxamide;(2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]aminehydrochloride;[(methylethyl)sulfonyl](2-{4-[4-(2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenoxy}propyl)amine;N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)acetamide;2-methyl-N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)propanamide;[(methylethyl)sulfonyl]{2-[4-(4-{2-[(methylsulfonyl)amino]ethyl)phenyl}phenoxy)propyl}amine;[(methylethyl)sulfonyl](2-{4-[4-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)phenyl]phenoxy}propyl)amine;4-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile;[(methylethyl)sulfonyl](2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenoxy}propyl)amine;N-acetyl-N-{3-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}acetamide;methyl4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoate;4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoicacid;[(2S)-2-(4-{3-[(methylsulfonyl)amino)phenyl]phenoxy}propyl][(methylethyl)sulfonyl]amine;[(2R)-2-(4-{3-[(methylsulfonyl)amino]phenyl}phenoxy)propyl][(methylethyl)sulfonyl]amine;and4-[4-((1S)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile;or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposltion, which comprises a compound according to claim 1 and apharmaceutically acceptable diluent or carrier.
 13. A method ofpotentiating glutamate receptor function in a patient, which comprisesadministering to said patient an effective amount of a compound offormula:

wherein R¹ represents an unsubstituted or substituted aromatic group, oran unsubstituted or substituted heteroaromatic group; R² representsisopropyl; R⁵ represents hydrogen; and R⁶ represents (1-6C)alkyl; or apharmaceutically acceptable salt thereof but excluding the compound[(methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxy]propyl}amine.14. A method of treating depression in a patient, which comprisesadministering to said patient an effective amount of a compound offormula:

wherein R¹ represents an unsubstituted or substituted aromatic group, oran unsubstituted or substituted heteroaromatic group; R² representsisopropyl; R⁵ represents hydrogen; and R⁶ represents (1-6C)alkyl; or apharmaceutically acceptable salt thereof but excluding the compound[(methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxy]propyl}amine.15. A method for improving memory or learning ability in a patient,which comprises administering to said patient an effective amount of acompound of formula:

wherein R¹ represents an unsubstituted or substituted aromatic group, oran unsubstituted or substituted heteroaromatic group; R² representsisopropyl; R⁵ represents hydrogen; and R⁶ represents (1-6C)alkyl; or apharmaceutically acceptable salt thereof but excluding the compound[(methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxy]propyl}amine.16. A method of treating Alzheimer's Disease in a patient, whichcomprises administering to said patient an effective amount of acompound of formula:

wherein R¹ represents an unsubstituted or substituted aromatic group, oran unsubstituted or substituted heteroaromatic group; R² representsisopropyl; R⁵ represents hydrogen; and R⁶ represents (1-6C)alkyl; or apharmaceutically acceptable salt thereof but excluding the compound[(methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxyl]propyl}amine.17. A method of treating psychosis or cognitive deficits associated withpsychosis in a patient, which comprises administering to said patient aneffective amount of a compound of formula:

wherein R¹ represents an unsubstituted or substituted aromatic group, oran unsubstituted or substituted heteroaromatic group; R² representsisopropyl; R⁵ represents hydrogen; and R⁶ represents (1-6C)alkyl; or apharmaceutically acceptable salt thereof but excluding the compound[(methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxy]propyl}amine.